New Drugs: Designing Novel Arylcyclohexylamines

[This article requires serious revision as I have been made aware of a great deal of data that I hadn't yet seen when I wrote this. There are many more moieties and specific moiety relationships that produce active compounds in vitro that are not mentioned as such here. I'll get around to it when I'm done some other projects!]

Preface:

Hello, This is the first in a new series I have been working on.

I have previously written a great deal on experiencing drugs firsthand and then on the properties of little-known substances. It was while investigating this that I realized the next direction to go- as a lot of these obscure substances were analogues of more familiar ones- interesting modifications on some basic themes, yielding variations that were for the most part obscure and novel. Drug design is both seemingly infinite in its possibility yet constrained to sets of rules within discreet categories. It is reading the paths that have been taken, and taking one step in a slightly different direction, and perhaps as your knowledge builds you can begin to reliably predict larger untested leaps of faith into more creative and curious designs. This requires recognizing patterns across fields of substances of recognizing which structures and combinations of structures will govern how our body will respond to said substance.

It is my hope that I have been successful in recognizing these patterns to the best of my ability and extrapolating from that. I would like to present ideas that I so far have not yet seen for producing novel psychoactive compounds of different properties. My main focus will be on hallucinogens, namely psychedelics and dissociatives.

My method to doing this is to assess all existing compounds within a class of chemical, not only those that have been on the consumer market but ones that are mentioned in passing as being active in literature, and ones that have so far only displayed activity in vitro or in other animals. From there, I can try and determine which properties may be shared across several different compounds with different structures. I can (hopefully) make educated guesses about the properties certain substituents generate and conserve across structures. I can try and presume that other structures that have not yet been attempted but are biologically analogous to known active structures will also be active- for example in psychoactive substances, different halogens can often be exchanged for one another and activity will be conserved- or in certain structures a sulfur can be exchanged for an oxygen with a degree of activity conserved. I hope what is written in this series proves to be useful in aiding the development of new compounds with a range of exploratory and therapeutic applications.

CONTENTS:

1. Introduction

2. A Flowchart for developing novel Arylcyclohexylamines

3. The Moieties

            -The Cyclohexane

            -Ring Substititions

            -The Amine

            -The Aromatic

            -A Footnote: Conformational Constraints

4. What to study from here?

 

Introduction

This first post is about dissociatives, specifically the class of compounds known as Arylcyclohexylamines. This class of compounds offers extremely diverse possibilities that for now are limited mostly only by the imagination. Perhaps someday clearer limits be determined. To demonstrate the absurd degree of possibilities, I made a handy flowchart that you can use to design a novel molecule! I then go into extensive detail on why I selected each component of this chart, under “The Moieties”. You can skip that part if you want. I finally go into what I would like to see in terms of development in this class of chemical, perhaps some ideas for an enterprising researcher.

One fairly obscure word I use a lot that would be good to know is “Moiety”- This is a general term that denotes some kind of defined structure within a molecule. You could consider a molecule an assemblage of different moieties. In this case, I use it to refer to the various structures within an arylcyclohexylamine that can be swapped out for other structures to create different effects.

So Arylcyclohexylamine. That’s a big word that I will be using a lot. What does it mean? What does it look like? If you are reading this you probably already know, you can skip the next paragraph. If you don’t know though:

It is perhaps best to understand the Arylcyclohexylamines by familiarizing yourself with some examples: Ketamine, PCP, MXE, 3-MeO-PCP, O-PCE, Deschloroketamine, MXPr. These are all well-known specifically as dissociative drugs, formally known as NMDAr antagonists. They produce physical analgesia and lead to interesting hallucinatory cognitive effects characterized by a pleasant depersonalization. Not all Arylcyclohexylamines act as dissociatives or are active compounds, but the majority of them that have been explored do. Some examples are opioids or stimulants.

 What denotes a molecule being an Arylcyclohexylamine? Its standard structure! What does that look like? Let’s break it down, which we can do by name. Aryl- refers to an aromatic ring, that is a ring structure with that allows electron flow freely throughout the entire ring, which locks its shape in place and creates an extremely stable structure. This is represented on molecular diagrams as a pattern of double bonds. The best-known example of this is the six-carbon benzene ring, referred to as a phenyl group when it’s a component of a larger molecule. -Cyclohexyl- meanwhile refers to the basic cyclohexane molecule, that is a ring of six carbons in a hexagon, single bonded to each other. It is possible that other compounds could be exchanged for the Cyclohexane; I speak more on that later in this post. Amine, meanwhile, refers to any organic molecule that contains a nitrogen single bonded to other atoms, in this case it is a nitrogen bonded to the cyclohexane ring with some other group extending from it. So that gives us an aromatic ring attached to a central cyclohexane ring, with an amine attached to the same spot as the aromatic ring. These compounds can then have substitutions- in the case of arylcyclohexylamines, substitutions are additional molecules attached to different places on the ring structures. These attachments often conserve activity but alter the specific effects each compound will have on a human subject. Herein lies the exciting sea of possibilities- as all different compounds known so far seem to be unique in their effects!

Arylcyclohexylamines have a standardized though informal nomenclature that lets you quickly determine the structure from the name of a compound. The names are structued X-YCZ. The X represents any substitutions, listed with the site they are attached to. A lone number denotes an attachment on the aromatic ring, a ‘ after the number denotes an attachment on the cyclohexane ring, and a “ denotes an attachment on any amine ring structures that may be present. The Y represents the aromatic ring. Typically this is represented by a “P”, as a phenyl is the most commonly used aromatic ring. The C will always be “C”, to represent the cyclohexane ring. The Z meanwhile represents the amine group, usually abbreviated to the first or first few letters. So PCP for example, is Phenyl-Cyclohexyl-Piperidine. 3-MeO-PCE is 3-Methoxy-Phenyl-Cyclohexyl-Ethylamine.

It has been documented that Arylcyclohexylamines can see a variety of alterations that conserve activity. The first place to look as the aromatic group- the vast majority of Arycyclohexylamines use a phenyl ring, but it is known that a thiophene ring can be active too. This opens two possibilities- that aromatic rings with either 5 or 6 members will remain active, and that aromatic rings with other atoms on them beyond carbon will remain active. Below the flowchart I will explain my reasoning in depth for selecting the possible aromatic rings that I did. The next modification can come on the amine moiety. A huge ocean of possibilities opens up here, with all sorts of structures yielding viable amines. It should be noted that it seems as though only fully saturated carbons directly adjacent to the nitrogen are tolerated. In other words, this means no double bonds anywhere near the nitrogen (with one known exception)! Otherwise, have fun.

Anywhere where you have a ring, you may hypothetically attach a range of substitutions- which range from alkanes, Alkoxy groups, Ketone oxygens, Hydroxy groups, Halogens, Halogenated alkanes, ethers, esters, ring structures, and possibly thioalkanes, all being available to strap onto rings at almost any available position, given they are substantially lacking in bulk and don’t create steric interference with other parts of the molecule.

Of course I’m not necessarily saying you can freely do all of this- unexpected exceptions and pitfalls arise everywhere. According to self-reporting by bluelight user “adder” for example, a 2’-Oxo substitution on PCP also yields an opioid-like compound, a substitution that is an active dissociative with a chain alkane as the amine. Sometimes it appears changes in substitutions or substituents give you unexpected shifts in which receptors the molecule will interact with. Nonetheless, rapid shifts in activity are for now, the exception and not the rule, and it seems the majority of them preserve dissociative activity so long as those basic components are fulfilled. While a lot of these structures have been studied and determined active in animals, that activity was often pinned simply to basic tests of analgesia, meaning the compound could behave either as an opioid or an NMDA antagonist. Tests like the capsaicin test or a naloxone inhibition test would help clarify.

It’s worth mentioning I have a very poor background in Organic chemistry. While I understand the rudiments of structural properties of molecules, synthesis and reactions are a foreign, incomprehensible world to me. I know nothing of what the process of actually producing any of these compounds is like, what the safety or viability or price or legality of any of that would be. I can not spot from afar which compounds may be synthetically impossible, prohibitively difficult or expensive, or which compounds may simply end up being unstable. I hope someone with more knowledge in that area can chime in- but for the time being I did not give synthetic viability any regard in my designs.

Before sharing this chart, I figure I should give a warning on potential danger. As you stray further and further from familiar compounds you may see more and more unexpected effects. You may be able to reliably predict a simple substitution modification on a compound with a phenyl ring and some familiar alkane amine. Not to say that such a compound can be immediately presumed safe, but I would say the chance is greater than with something much more experimental. Say you are running with something that has no known immediate analogues for reference- for example’s sake, 3-TFM-FCEBF. Refer to the chart for the structure of that one. But nothing very similar exists- we don’t know what exactly a furan ring as the aromatic does, what a Trifluromethane substitution does or an ethylbenzofuran amine. What would be the safest way to approach such a compound?

There are also a number of ways chronic toxicity is reported to present with NMDA antagonists, mainly neurotoxicity and cytotoxicity. In terms of neurotoxicity, there are the infamous Olney’s lesions, a form of brain damage, that has been observed in other animals, though they have still not officially been observed in humans yet [43]. However, a recent study reportedly observed some form of damage in the brain of extremely frequent users of ketamine [44]. The other main reported symptom that indicates toxicity is urinary toxicity [45, 46], supposedly a result of damage to the epithelial cells lining the bladder caused by direct toxicity from ketamine metabolites. This has so far only been officially reported with ketamine, though there are anecdotal reports of it occurring in frequent users of other dissociatives. There is also a potential for cognitive dysfunction from extreme repeated use of dissociatives, mostly in the form of “brain fog” and memory loss, though there is some literature on the matter [47].

These substances also carry the risk of generating dangerous behaviors that can be damaging to one’s life circumstances and relationships, both through the dangerous interplay of prohibition and substance, and in properties inherent to the chemicals themselves. One key risk is addiction- while physical dependence to dissociatives is significantly more rare than with other classes of substance, it is entirely possible and psychological dependence is commonly reported. Frequent usage significantly increases the chance of toxic effects or cognitive dysfunction presenting. Other substances, such as PCP, are notorious for causing intense mania that can push into psychosis, which can lead to violence, damaging relationships, and legal trouble. All of these risks are real and it is up to the user to determine what methods personally work best for mitigating them, including total abstinence if necessary.

I would suggest, in a perfect world (keep in mind this is all very handwaved, this actual process can be expensive, difficult, and extremely time consuming)- First, doing a virtual docking simulation of the compound. This of course is not a surefire way to determine activity, but can perhaps give warning of possible unexpected activity or help to rule out certain options as being less viable. The compound can be synthesized from there, at which point it must be properly characterized via NMR and GC/MS analysis. From there, an in-vitro receptor affinity study can be done to confirm or deny certain targeted activities in nerve cells in comparison to familiar reference compounds, like PCP, Ketamine, MK-801 or Morphine. The safest step from there would be in-vivo studies in animals, also compared to a control group of reference compounds. Behavioral tests can be done for comparison to any references, and drug substitution tests can help indicate similarity to the references. There is a huge variety of animal tests that can be done in combination with each other and with various controls to really narrow down possible mechanism of action depending on what a researcher has at their disposal. In-vivo tests also help to determine an mg/kg dosage range and possible acute or chronic toxicity, or even an LD-50. Only after it has been presumed nontoxic and its likely activities have been characterized should one even consider human testing. This must also be done in the context of extremely precise doses, titrated upwards from a microgram range, with the subject physically monitored by a healthcare professional. If you want to get really fancy, this can be performed in a double blind test with a placebo.

Of course not all those processes or resources are available to every researcher. Those are all long, difficult, expensive processes that may require specialty equipment, facilities, and faculty. Many researchers of psychoactive compounds have opted to skip some or most or all of those steps, and prohibition absolutely makes obtaining any of those resources extremely difficult. I would recommend approaching with maximum caution, but I’m also not the boss of anyone and can’t make anyone do anything, and understand how the spirit of curiosity can sometimes overcome a lack of available resources. Ideally a team of researchers could easily have infrastructure to efficiently run multiple compounds through that gauntlet of safety determinations. But this world is less than ideal. Please just for the love of god, be safe, be smart, be responsible.

A flowchart for developing Novel Arylcyclohexylamines

You can enlarge the image here:

https://i.imgur.com/DcKXhv6.png

You can find a pdf version of this chart here:  

https://gofile.io/d/nspZWa

That was a doozy.

So what about each and every substitution and substituent? Fuck, this is my blog, I can do what I want and write what I want and make a post as long as I want. This will probably not be interesting, but it’s a form of data, here we go:

THE MOIETIES:

The Cyclohexane (and others):

We start with looking at the Cyclohexane Ring-This is the one consistent component in Arylcyclohexylamines. It’s right there in the name. But-there is evidence it is not our only option! I mention this in the footnotes of the chart, and as this article is on Arylcyclohexylamines, all other moieties and substitutions I mention will be under the assumption of being anchored on an arylcyclohexylamines. For the sake of interest though, I will briefly mention those other possibilities. It should be noted that derivatives of the following compounds would technically not be Arylcyclohexylamines as a result of them not having a cyclohexane group. An alternative game is given after each possibility, and this entire series of structures and their derivatives could broadly be referred to as Aryl[x]amines. I may bring attention to these in a future article, as I think it is highly worthy of consideration and shouldn’t just be buried in this post. Anyways:

Thiane- Arylthianylamine: A Thiane ring, that is a Cyclohexane if you replaced one of the carbons with a sulfur. It appears with this type of substitution, it is best to keep the electronegative atom as far from the aromatic/amine bond as possible. If I remember my naming conventions properly it would be 3-[Aromatic],[Amine]-Thiane, with the sulfur at the 1 position. This structure was alleged on a bluelight thread, where a user stated that they remembered reading a study that found evidence of activity in a EJoMC article, but were unable to find the article anymore. One active compound cited by this use was a thiane derivative of PCiPr, you could call it PTiPr if you’d like. Despite the lack of evidence for now, It’s an interesting hypothesis and nothing stands out to me that would invalidate it. If anyone can find more information on this please let me know!

Oxane- Aryloxanylamine: As I will state several times throughout this article, an oxygen can sometimes be substituted for sulfur to retain bioactivity in many molecules, as they have similar binding properties. Though there has been 0 published conjecture on this, I believe it remains as a possibility.

Adamantane- Aryladamantylamine: Described in [13], this is a very very interesting variation, with the complex 3-dimensional adamantane serving as the central structure, the aryl and amine bonded to one location on one of the cyclohexane rings that composes its form. Interestingly, adamantanylamines compose their own class of dissociative, with the simplest Amantadine, and the dimethylsubstituted Memantine being very non-potent but ultimately powerful dissociatives. So perhaps its intuitive to combine the two classes. This one study found lower toxicity (you can read that as lower potency perhaps) but enhanced anesthetic effect relative to PCP [13]. Very promising- an adamantane also has several potential locations for substitutions. This would open the door to dizzying possibilities.

Bicyclo-Heptane (Arylbicycloheptylamine): Described in [10], another 3d polycyclic structure like adamantane, but toned down a bit. The particular compound that displayed activity had an ethyl-piperidine attached to the amine site, an interesting and unique substitution. This structure is also called Norbomane.

Tetralyl (Aryltetralylamine): Shown in [2], where a Tetralyl (That is two conjoined six member rings- a cyclohexane and a phenyl) analogue of 3-Meo-PCP is presented. In the animal trials, it was shown to act as an analgesic with specific properties that indicate it may function more as an opioid instead of a dissociative- nonetheless it’s an interesting avenue for development that may be open to all kinds of substitutions. Having an aromatic butted up directly against the cyclohexane surely has some interesting implications for activity.

 

Alternative structures to a cyclohexane

Now that that’s out of the way, lets get to the meat of things.

Ring Substitutions:

From here on out, it is assumed that we will be using a cyclohexane ring, producing a true Arylcyclohexylamine.

The first thing we’ll look at are the available ring substitutions. There are a lot of potential options! The general rule for known substitutions that can conserve NMDA activity are: Alkane chains, Ether chains, Hydroxy, Ketone Oxygen (only on a saturated ring!), Amine, Halogens, Halogenated Alkanes, Halogenated Ether chains, Aromatic Rings, Esters, and hypothetically thioalkane chains. Substitutions can be placed on any ring structure, whether it be an aromatic, the cyclohexane, or any ring structures on the amine. Whichever ring it is determines which substitutions will work- something that helps is to know how molecular diagrams work- pretty much any carbon on the ring that has an open hydrogen can have that hydrogen swapped for some other substitution. In general, it seems that substitutions on the 3-position of an aromatic ring, a 2’-Oxo substitution, and substitutions on the para-position of other amine ring structures show the most promise.

I have proposed several options for substitutions that appear viable- lets dissect them a bit.

Alkane substitutions:

Me (Methyl): The simplest carbon and 3-hydrogens. The Methyl substitution is well understood to conserve activity, and in some cases it even brings about activity where it did not exist in the base structure [4]. I will not even cite all the sources here because they are too varied, but placing Methyl substitutions on at least one position on every viable ring seems to conserve some kind of activity, depending on what other substitutions are lurking about. Proceed with this one confidently.

Et (Ethyl): [19] and [24] both show an ethyl substitution, but in the unique place of a. being a substitution on the piperidine ring of PCP, and b. sharing that substitution site with something else, typical a methyl group. These were demonstrated to be active, but the exact method of determining that activity and whether that’s NMDAr antagonist or Opioid activity still remains to be seen. Such changes in activity would likely come from jamming two substitutions onto one carbon though, not anything inherent to the ethyl group, which by all means seems normal and benign. I would most like yo see it as a 3 position substitution on a phenyl ring, to just help establish what the SAR pattern of extending alkane chains may be like.

Pr (Propyl): I don’t see why this wouldn’t work but it hasn’t been attempted yet. A 3-Pr substitution on a phenyl ring would probably be the best place to start.

iPr (Isopropyl): I don’t see why this wouldn’t work but it hasn’t been attempted yet. A 3-iPr substitution on a phenyl ring would probably be the best place to start.

cP (Cyclopropyl): In several other psychoactive molecules, a cyclopropane can often stand in as a possible substitution. It has never been attempted on an arylcyclohexylamine so its effects within that context are for now, unknown. But It’s possible! Once again, a 3-cP substitution would be the best place to start.

Bu (Butyl): In other psychoactive molecule series, there is a steep drop in potency when an alkane chain gets too bulky- 4 carbons usually seems to be it. I don’t look into any aliphatic alkane longer than this, but a butyl substitution remains a possibility, best at the 3 position. However, this is evidence that a bulkier substitution may actually lead to an increase in potency, at least for PCP (see BuO substitution)

iBu (Isobutyl): An isobutyl would probably be similar to a Butyl chain, but less bulky. This may show ore promise than a straight butyl chain in fact. Best at the 3 position.

sBu (sec-Butyl): Another configuration that may show promise. Also best at 3 position.

tBu (tert-Butyl): With a tert-Butyl structure you run the risk of inactivity due to steric interference of so many carbons crammed so close together. This leads to compounds that may be unstable or are exceedingly difficult to manufacture. I wouldn’t put much stock in tert-butyl substitutions being possible or active, but I included it for completion.

Ether Substitutions:

MeO (Methoxy): This is a classic substitution that has clear demonstrated activity in a variety of structures and when combined with other substitutions. Combination with a 2’-Oxo group has produced a line of well renowned compounds like MXE or MXPr. 3/4 substitutions on the phenyl ring are clearly active, as in 3-MeO-PCP. A 4’ substitution on the cyclohexane may be promising, a would a 3”/4” substitution on say, the piperidine ring of PCP. More experimental data also see it strapped on to all sorts of compounds with outlandish amine structures. There is evidence that it retains activity when substituted onto a Piperidine ring [6] opening that ring up for more possibilities. Seems to offer a lot no matter where you pit it.

EtO (Ethoxy): Similar to the Ethyl vs. Methyl group, this hasn’t been attempted but I see no reason it wouldn’t work. [32] saw a compound with a butoxy group retain in vitro activity, so I imagine everything between methoxy and butoxy could be active. Best to start on the 3 position again.

PrO (Propoxy): Hasn’t been attempted but is a likely candidate. See above.

iPrO (Isopropoxy): Hasn’t been attempted but is a likely candidate. See above.

BuO (Butoxy): PCP analogues with 3 and 4 BuO substitutions were found to be not only active but potentially highly potent in an in vitro study [32]. This suggests several interesting ideas: The first is that everything alkoxy group between a Butoxy and a Methoxy in length on the 3 or 4 position would be active. The second is that a bulkier substitution actually leads to an increase in potency. Psychoactive substitutions usually cap off around a pentane but perhaps with arycyclohexylamines it is worth exploring further.

iBuO (Isobutoxy): Same idea as a Butoxy group- I can see the various rearrangements of the butane isomers as maintaining similar properties when bonded to the 3 or 4 position.

sBuO (sec-Butoxy): Same idea as a Butoxy group- I can see the various rearrangements of the butane isomers as maintaining similar properties when bonded to the 3 or 4 position.

tBuO (tert-Butoxy): Same idea as a Butoxy group- but with the same stipulations as mentioned with a tert-butyl group before. If this did work/was stable/was feasible to produce it would certainly be interesting.

Hydroxy Substitution:

HO (Hydroxy): This little substitution has been placed on the 3 position of the phenyl ring for a handful of familiar compounds with exciting results. People have proposed combining it with a 2’-Oxo group ala MXE and friends, with the 3-HO group replacing the 3-MeO group. There is promise in this, and such compounds have been promised for years, but their existence for now seems to remain a rumor or confined to a very tight market. A number of researchers have sought to explore the role of an -OH on the piperidine ring of a PCP (most notable a pcp metabolite excreted in urine is 4”-HO-PCP aka PCHP, I don’t know if its psychoactive in its own right though). There are a dizzying amount of study compounds with this, which really suggests this is a substitution that can be wantonly thrown around to maintain activity. Play around with it. Some examples can be seen in [1, 3, 9, 14, 19]

Oxygen Substitution:

Oxo (O): This is an oxygen double bonded as a substitution, turning the compound into a ketone. It’s a highly notable substitution, most notably appearing in the ketamine molecule. An Oxo group can only be placed on a fully saturated ring structure- so far we’ve only seen it on cyclohexane and piperidine/pyrollidine bases, but perhaps it could be placed on a saturated side chain amine ring structure. Almost everywhere this substitution has been seen has placed it on the 2’ position on the saturated middle ring. This is seen in Ketamine, DCK, 2F-DCK, O-PCE etc. Supposedly, when attached to PCP it becomes more of an opioid with negligible dissociative effects [33]. A 4’-Oxo PCP substitution was also attempted, which was similar [33]. Adder, author of that thread, suggested that a bulkier amine paired with an x’-Oxo substitution would reduce NMDA activity. Indeed 2’-Oxo-PCM (DCK) and 2’-Oxo-PCE (O-PCE) are very clearly dissociatives. Because it is fairly unique as far as arylcyclohexylamine substitutions go with weird activity patterns, this is one that should be treated with caution, especially when pairing it with unfamiliar amines or attaching it to different locations on the cyclohexane ring- or dare I say placing it on a saturated amine ring- maybe inactivity, maybe something entirely unexpected- hard for me to discern.  

Thioalkane Substitutions:

MeT (Methylthio): This is pure Hypothetical territory running on the principle that you can sometimes swap an oxygen for a sulfur in structures and retain activity. This is the realm of someone who understands pharmacology better than me but I figure I could at least suggest it. A 3- position substitution would be safest to try first.

EtT (Ethylthio): More pure conjecture but from  multiple angles now- two purely hypothetical ideas unite here. I can’t say anything on this really other than it should also be tried on a 3- position.

PrT (Propylthio): Same as before, perhaps the hypothesized pattern with potency seen in the alkoxy compounds would apply to the thioalkanes too. But that is truly nothing more than a wild guess. I would say one should figure out if a sulfur does anything in the first place before starting to venture into longer chains or different isomers.

Amine Substitution:

A (Amino): What gives, arylcyclohexylamines already have an amine! Well here’s another, but elsewhere. Bluelight user adder stated a 3-Amino substitution was effective [33]. Several other studies have found this compound active and potent, including the big old assessment by Kalir in 1981 [19]. This can be assumed a green light for development! Synthetic difficulties aside.

Halogenated Substitutions:

F (Fluoro): This was first seen on the market in 2F-DCK, where it replaced what is ordinarily a chlorine in ketamine at the 2 position. It appears activity is still retained when the oxygen is removed from the cyclohexane ring, suggesting that a simple 2-substituted halogen will hold up in that situation. Fluorine has also been attempted on the 3 position on PCP- an interestingly novel but fairly lackluster dissociative with a pretty low potency. I am curious about how this would function with other amines. Halogens in general seem to kill potency, but still create worthwhile compounds that you just need more of. Fluorine is a good basic one to start with and lay out patterns. Placing it at the para position of another ring also seems like it may work. Apparently a 4-F substitution is inactive [33].

Cl (Chloro): Things seem to stay active as we sit at the top of the periodic table. This substitution is most notably in ketamine, on the 2 position. As said before, a 2-chloro substitution without the oxygen on the cyclohexane still appears to be active. This is certainly an interesting route to explore. A 3-Chloro PCP analogue has also come out recently, and though I haven’t been able to try it as of this writing, initial reports claim it is similar to 3-F-PCP in potency and experience. As before, para substitutions may be another way to go with this one.

Br (Bromo): Adder didn’t see much promise in the halogenations as you went down the table, labeling 3-Br-PCP as inactive [33]. I think it is worth revisiting however. A bromo substitution is fairly easy from what I understand and a logical route to go when testing halogens. It likely would require a very high dose- perhaps outside the range of the chemicals being tested in that thread. Activity in the lower halogens suggest that a 3-Br substitution would continue that pattern but things are also hard to predict. I imagine it would work best on the 2 or 3 position.

I (Iodo): Purely hypothetical, hasn’t been attempted. If 3-Br-PCP is inactive, 3-I-PCP definitely is. I would imagine that if it was active it would require a massive dose for activity. It is probably most effective on the 2 or 3 position if at all. Iodine can be seen as conserving activity in some psychoactive drugs, namely psychedelics like 2C-I or 25I-NBOMe.

TFM (Trifluoromethyl): Purely hypothetical but such a reactive group is always an interesting avenue when it comes to substitutions and I surely think it is worth trying as an arylcyclohexylamine. I would suggest only trying this on the 3 or 4 position of a phenyl ring or the 4” position of a piperidine ring for now.

TFE (Trifluoroethyl): A slight variation on the same as above. I figure the same properties would stand.

Halogenated Ether Chains:

TFMeO (Trifluoromethoxy): This is based on the compound following this, which features the trifluoromethane bonded directly to the oxygen. Whether it would work so close to the oxygen may be up for debate. I don’t have much faith in this one.

TFEtO (Trifluoroethoxy): This substitution was demonstrated to be mostly active in vitro in [32]. This seems a really out of left field idea for a substitution as far as I know, but hey, it seems feasible. Perhaps that extra carbon keeping the intense bristling fluorines away from the oxygen stabilizes its activity a bit. It was tested on the 3-position of the phenyl ring in PCP, I wouldn’t stray further from that if attempting this.

Aromatic Ring Substitutions:

Ph (Phenyl): Strapping on an entire new aromatic group as a mere substitution seems absurd- could you perhaps attach substitutions to this? Nonetheless several active compounds have been discovered in vitro from this odd substitution, mostly on the Piperidine ring of PCP. Some of these compounds are also suggested to be opioids, so be wary! They can be seen in [9, 16].

Bn (Benzyl): Who knows what a Benzyl group as a substitution would do, but the possibility is on the table. If a phenyl can retain some activity, a Benzyl might too? But I would perhaps expect an opioid to come from this.

Ester Substitutions:

AcO (Acetoxy): al Deeb et al [9] demonstrated a variety of odd compounds that were analogues of TCP. Most of these featured a double substitution on the 4”-position of the piperidine ring, with obscure phenyl groups, but more importantly with a series of esters that despite their large structures retained activity. A 4”-AcO-TCP proved to be the second most potent compound of this series. These compounds varied in suggested opioid vs. NMDA antagonist activity. Whether ester substitutions would work on other rings in the arylcyclohexylamine compound is entirely unknown- for now I would suggest just developing along 4-Piperidine analogues.

PrOa (Propanoate): A larger ester that also demonstrated activity in al Deeb et al [9]. Also sufficiently active. Whether ester substitutions would work on other rings in the arylcyclohexylamine compound is entirely unknown- for now I would suggest just developing along 4-Piperidine analogues.

iPrOa (Isopropanoate): Conjectured ester that retains activity based on what other active esters are. I see no reason this wouldn’t work. Whether ester substitutions would work on other rings in the arylcyclohexylamine compound is entirely unknown- for now I would suggest just developing along 4-Piperidine analogues.

BuOa (Butanoate): Conjectured ester that retains activity based on what other active esters are. I see no reason this wouldn’t work. Whether ester substitutions would work on other rings in the arylcyclohexylamine compound is entirely unknown- for now I would suggest just developing along 4-Piperidine analogues.

BnO (Benzoate): The bulkiest and most complex ester substitution put forth, which demonstrated the highest potency of the entire series attempted in [9]. A promising route. Whether ester substitutions would work on other rings in the arylcyclohexylamine compound is entirely unknown- for now I would suggest just developing along analogues where the substitution is found on the 4-position of the piperidine.

MD (Methylenedioxyl): This is a substitution that for now will probably show the best results bonded to the 3,4 position of a phenyl ring (as the aromatic). There are other positions and other rings where it can be wedged in but a 3,4 substitution shows the most promise. A 3,4-Methylenedioxy group is best known as a component of MDMA. But that has no relation to an NMDA antagonist beyond a shared substituent. Nonetheless, it can be expected that at the very least, bioactivity an be conserved with this substitution.

Fu (Furanyl): Similar to the last, I am really only accounting for it being bonded on the 3,4 position of a phenyl ring, forming the famous benzofuran group found a variety of unrelated psychoactive substances. If there was any ring shaped substitution that would present activity beyond a 3,4-MD group, I would suspect it would be a Furan, forming a benzofuran.

THF (Tetrahydrofuranyl): Purely conjectural. Probably should also only be placed as a 3,4 substitution.

THP (Tetrahydropyranyl): Purely conjectural. Probably should also only be placed as a 3,4 substitution.

 

Now we get to the meat of the meat- let’s dive into the vast vast diverse field of Amine Moieties. This will be long. Sit back.

 

The Amine

Denoted by the tail end of the term “arylcyclohexylamine”, we find ourselves at perhaps the most diverse avenue for variation on this molecular backbone. The amine allows for a dizzying diversity of possibilities. For a quick lesson- a amine is a nitrogen bonded to carbons. Nitrogen typically only can bond with three things at a time. A primary amine is a nitrogen bonded to a carbon structure and two hydrogens, a secondary amine sees it bonded to two carbon structures and one nitrogen, and a tertiary amine sees it bonded to three carbon structures. The choices I made were determined by a few observations I had made on patterns, like

-It appears that any carbons directly adjacent to the amine must be saturated. Thus a enamine would not be active but an allyl would. This also manifests in ring structures, where it appears an aromatic tertiary amine ring should not be tolerated- however in [5] it was found that a pyrrole group could conserve activity only if it was paired with a methyl group on the phenyl ring. Curious, but a researcher may find more success exploring the saturated ring structures for now.

-In a Tertiary amine, a bulky substituent paired with a smaller one seems to reduce activity (eg; some long ester paired with a methyl group as seen in [17]). It makes sense to keep these to modest alkane chains for now.

With this in mind, I set out to list out which viable possibilities I could brainstorm:

Primary Amine:

-A (Amine): The simplest option we have on hand, the base primary amine where the nitrogen sits alone with its two hydrogens. When paired with the 2-Cl-2’-Oxo substitutions of ketamine, it is known as norketamine, which is one of the many metabolites of ketamine in the human body. Evidence suggests however that norketamine is active in its own right [31]. This opens the door to other variations on this structure.

Alkane Chains:

Alkane Chains are the simplest substitutions you can add to an amine on an arylcyclohexylamine. They are reliably active and are known to tolerate a variety of substitutions. Most of our known familiar compounds that have hit the market (Ketamine, DCK, 2F-DCK, MXE, O-PCE, 3-MeO-PCE, 3-HO-PCE, MXPr, MXiPr etc.) are variations on simple alkane chain amines.

-M (N-Methylamine): A methyl group is the simplest alkane that can be strapped to an arylcyclohexylamine. It may perhaps be the basis for the most familiar arylcyclohexylamine, namely ketamine, which could also be known as “2-Cl-2’-Oxo-PCM”. PCM and its analogues are by far the best studied of the arylcyclohexylamines. With the variety of other compounds like 2F-DCK, DCK, MXM etc., it can be assumed that a methylamine will tolerate all sorts of variations, a stable base that can be consistently trusted to deliver worthwhile compounds.

-E (N-Ethylamine): An Ethyl group is another tried and true amine. The unsubstituted form, known as PCE, is potent and was once upon a time sold on the street as an alternative to PCP [26]. Several other very well known compounds use this base, most notably MXE, or 3-MeO-2’-Oxo-PCE. 3-MeO-PCE is a personal favorite of mine, and many others have found favorites among the various PCE variations. With the sheer amount of substitutions and combinations of substitutions that are possible, it’s likely that PCE will always be a gift that will keep on giving for drug development.

-Pr (N-Propylamine): Developing alkane substitutions follows a predictable path of just adding one carbon at a time, and here we are with a propylamine. It’s certainly active, though this has only been demonstrated with 3-MeO-2’Oxo-PCPr, also known as MXPr. Other substitutions would almost certainly see some sort of interesting activity. I conjecture they may show lower potency than their PCE counterparts however. Contrary to that however, [33] mentions that the base PCPr was similar in potency to PCP.

-iPr (N-Isopropylamine): Pretty much same as above, reconfigure the propylamine and you get another active compound, as demonstrated in MXiPr (3-MeO-2’Oxo-PCiPr). [33] mentions that the base PCiPr was similar in potency to PCP. Lots of room for variation here, we’ve only scratched the surface! Best to keep on chugging.

-Bu (N-Butylamine): Logically the next step is of course a butyl, 4 carbons. Adder in his bluelight thread on PCP analogues gave this one a passing mention as being active but less potent than PCP [33]. This raises a curious pattern- if the PCPr analogues are also suspected to show a drop in potency relative to a group with less carbons, it can be conjectured that you see potency go down as you extend the alkane chain. To that end I would hypothesize that you would see serious diminishing returns in potency once you go past a butyl, similar to substitutions on psychedelics. However, it is clear that bulk of the amine alone doesn’t determine potency, as some very large and bulky amines are not only tolerated for conserving activity, but are actually quite potent, like PCP for example. Fairly long reverse esters also conserve activity, but this might be due to being prodrugs for something else. So I would feel comfortable saying that there is an inverse relationship betweem amine bulk and potency only in the non-cyclic alkanes.

-iBu (N-Isobutylamine): This has never been attempted but I see no reason it wouldn’t work.

-sBu (N-sec-butylamine): This has never been attempted but I see no reason it wouldn’t work.

-tBu (N-tert-butylamine): This has never been attempted. Tert-Butyl groups can be tricky to work with synthetically so I’m not sure about the physical feasibility of this one. But if it can be made I would imagine it and its analogues would be active.

Amine Ether Alkane Chains:

Some enterprising users on theehive found out that NMDA antagonist activity is conserved in ether amines, which is laid out in detail by Hamilton Morris and Jason Wallach in [26], where such compounds are referred to as Arylcyclohexylalkoxyamines. Such compounds were apparently available on the market in Europe for a brief time. If I had invented this series I would’ve chosen a different set of naming conventions for them, at least something in the name to indicate that they are ethers or an oxygen is involved somewhere. Someone else already began naming them however, and thus all the hypothetical ether amines I present follow their conventions. Their method seemed to just be the letter for the chain after the oxygen, the chain before the oxygen, and an A to indicate the amine. Whatever I guess.

-MMA (N-Methyl-Methoxyamine): For now I consider the whole series of N-methyl ethers to be dubious in activity, based on a sort of unfounded gut instinct that having the oxygen too close to the nitrogen reduces activity. It is suggested in Jose et al 2013 [17] however that potency is a function of the size of the chain after an oxygen rather than between the oxygen and nitrogen. But that was also with reverse ethers, so who knows. For now I would say the N-methyl ethers are all possible but dubious.

-EMA (N-Methyl-Ethoxyamine): See above- possible but dubious.

-PMA (N-Methyl-Propoxyamine): See above- possible but dubious. I only go as far as a propyl chain extending past the oxygen. Maybe arbitrary, but I feel like diminish returns would come from strapping longer chains there.

-iPMA (N-Methyl-Isopropoxyamine): See above- possible but dubious.

-MEA (N-Ethyl-Methoxyamine): This is a confirmed active moiety. How it may interact with ring substitutions elsewhere in the structure is unknown, but this PCMEA was apparently an active compound on the market at one point in time. It had enough potency and activity to be sold, but there exists little information on what the actual experience was like. It is mentioned in [26].

-EEA (N-Ethyl-Ethoxyamine): This is a confirmed active moiety. How it may interact with ring substitutions elsewhere in the structure is unknown, PCEEA was apparently an active compound on the market at one point in time. It had enough potency and activity to be sold, but there exists little information on what the actual experience was like. It is mentioned in [26].

-PEA (N-Propyl-Ethoxyamine): If PCMEA and PCEEA are active I see no reason for PCPEA to not also be.

-iPEA (N-Isopropyl-Ethoxyamine): If PCMEA and PCEEA are active I see no reason for PCiPEA to not also be.

-MPA (N-Methyl-Propoxyamine): This is a confirmed active moiety. How it may interact with ring substitutions elsewhere in the structure is unknown, PCMPA was apparently an active compound on the market at one point in time. It had enough potency and activity to be sold, but there exists little information on what the actual experience was like. It is mentioned in [26].

-EPA (N-Ethyl-Propoxyamine): PCEPA is mentioned in an analytical and pharmacokinetic study published in 2006 by Sauer et al [28]. This study seems to contextualize it as a novel drug of abuse, which is curious as I could find no other evidence of its existence or use. None of that work would’ve been done if it was inactive though, so its definitely worth investigating further.

-PPA (N-Propyl-Propoxyamine): If PCMPA is active I see no reason for PCPPA to not also be.

-iPPA (N-Isopropyl-Propoxyamine): If PCMPA is active I see no reason for PCiPPA to not also be.

-MBA (N-Methyl-Butoxyamine): Now we’re getting into unknown territory. If my arbitrary conjecture about activity being conserved in the distance between the nitrogen and oxygen holds up, then this should certainly be active. But I simply do not have enough knowledge to predict that.

-EBA (N-Ethyl-Butoxyamine): Same as above.

-PBA (N-Propyl-Butoxyamine): Same as above.

-iPBA (N-Isopropyl-Butoxyamine): Same as above.

Other Oxygenated Alkane Chains & Esters:

Here’s some other structures with oxygen in them. Most of these are pure conjecture, sorry.

-HOMA (N-Methyl-Hydroxyamine): Per the hypothesis I mention in the N-Methyl ethers, I wonder if it would still stand for a hydroxy alkane? Who knows. This one is probably conjecture for now.

-HOEA (N-Ethyl-Hydroxyamine): This is an active moiety This is demonstrated in [17], and then mentioned in [26] as having been on the market at some point too, the product of some bees on theehive and a brief flash in the euro market. No information on how it interacts with other substitutions or what the actual experience is like however.

-HOPA (N-Propyl-Hydroxyamine): A hypothetical moiety that’s never been attempted, if one wanted to explore further with hydroxyalkane amines I would think it would make more sense to go in this direction vs. in the direction of a methyl if the ethyl hydroxyalkane is the reference point. Perhaps a butyl chain would function too. There simply isn’t enough data to confidently guess.

-AcAL (N-Acetalamine): Pure conjecture. Nothing screams inactivity about this to me though. This is where pharmacokinetics come into play- I really do not understand pharmacokinetics and I am not sure if there is some obvious metabolic activity in response to an aldehyde that would render this either inactive or highly toxic. Someone who knows their stuff better than me should approach this one.

-PrAL (N-Propanalamine): Pure conjecture. Nothing screams inactivity about this to me though. This is where pharmacokinetics come into play- I really do not understand pharmacokinetics and I am not sure if there is some obvious metabolic activity in response to an aldehyde that would render this either inactive or highly toxic. Someone who knows their stuff better than me should approach this one.

-MAcO (N-Methyl-Acetoxyamine): The standard acetoxy ester on an ethyl chain is active in vitro, as a short acting compound (more on that in a bit). Would a methyl acetoxy group do the same? Acetoxy groups are well known as substitutions on tryptamines that yield unique and lovely effects. Not that that has anything to do with arycyclohexylamines, an entirely different class of drug with entirely different pharmacology.

EAcO (N-Ethyl-Acetoxyamine): This was demonstrated as active in [17], the only “forward” ester that was produced in a series of “reverse” esters that were tested alongside it. It was produced as a ketamine analogue (that would be 2-Cl-2’-Oxo-PCEAcO), and was shown to be the most potent in the series, with similar properties to the others in terms of rapid metabolism and action and short duration. Opens the door to more variations on this theme perhaps.

Reverse Ester Alkane Chains:

This is an interesting and obscure series of compounds that have not yet been tried in humans. First to clarify some terms- an ester is an organic functional group that sees an alkane chain meet an oxygen, which is in turn bonded to another carbon with a double bonded oxygen, which is in turn bonded to a further alkane chain. Just google it it’s hard to explain. Looking at the flowchart however, you will see that this series of compounds does not fit that description- these are “reverse” esters. What you call the front and back end of an ester is really just a matter of semantics. The side that connects to the bridging oxygen is is typically the “front” and the side that extends from the carbon that bears the -Oxo group is the “back”. Basic sense would dictate that you would call the larger more complex side the “front”, as is done with these compounds, thus the ester appears in reverse, with the big complex arylcyclohexylamine on the side of the chain with the -Oxo group, and a small alkane chain extending from the bridging oxygen. You could see these as a forward ester if you consider that little alkane bit to be the “base” of the structure and the entire unwieldly arylcyclohexylaine as the tail, but its harder to describe it that way, so they are just referred to as reverse esters. Semantics.

Anyways, weird nomenclature aside, these compounds have really interesting properties! All of them were produced in the context of ketamine analogues (meaning they had 2-Cl-2’-Oxo substitutions)[15] [17]. In that case, they seem to consistently produce extremely rapid and short lived experiences (in mice), with relatively low potencies. This doesn’t sound the most fun for the recreational user but has interesting possibilities for medical purposes. Certain compounds saw experiences that lasted even shorter than ketamine by several magnitudes [17]. What would be interesting would be to see how these compounds behave on their own without any substitutions and the implications that would have for potency and duration. After all, a 2-Cl substitution is known to greatly decrease potency. This may be of interest to someone out there, and it is worth fiddling with the structures in ways that would increase potency, perhaps by swapping the phenyl group for a thiophene, or as mentioned before, leaving it wholly unsubstituted?

[17] lays out that activity seems to be conserved as a function of the alkane chain extending past the oxygen, and that there was no correlation between potency and the distance between the oxygen and the nitrogen. It appears that building up to and past a straight propyl chain after the oxygen causes a steep drop in activity. I am going to take their word for it and my conjectures on activities are based on that.

-MAc (N-Methylacetate-amine): Of all hypothetical esters presented here I would consider this to be the least likely to be meaningfully active or potent. But it still may be. No one knows until they try.

-EAc (N-Ethylacetate-amine): See above. I would guess the chance of activity and increased potency increases as you extend the alkyl chain after the oxygen. Just a guess though.

-PAc (N-Propylacetate-amine): See above. I would guess the chance of activity and increased potency increases as you extend the alkyl chain after the oxygen. Just a guess though.

-iPAc (N-Isopropylacetate-amine): See above. I would guess the chance of activity and increased potency increases as you extend the alkyl chain after the oxygen. Just a guess though.

-MPOa (N-Methyl-propanoate-amine): See below. I see no reason this wouldn’t work. Other moieties with a methyl after the oxygen seem to work fine. Other propanoate amines conserved activity too.

-EPOa (N-Ethyl-propanoate-amine): Now we get into real activity. Most of the basic variations on adding an alkane chain to a propanoate were attempted in animals and seemed to serve as a baseline for developing other reverse esters as analgesics. This was a short acting rapidly metabolized compound that demonstrated analgesic activity in mice. It was about half as potent as ketamine [17].

-PPOa (N-Propyl-propanoate-amine): Another one active in mice, similar properties to the others with respect to duration. This was significantly less potent than ketamine [17].

-iPPOa (N-Isopropyl-propanoate-amine): Another one active in mice, similar properties to the others with respect to duration. This was the most potent of the pronanoate series, but was still less potent than ketamine [15] [17].

-MBOa (N-Methyl-butanoate-amine): See below. I see no reason this wouldn’t work. Other moieties with a methyl after the oxygen seem to work fine. Other butanoate amines conserved activity too.

-EBOa (N-Ethyl-butanoate-amine): Another one active in mice, similar properties to the others with respect to duration. This was some close to ketamine in potency, though ultimately less potent [17].

-PBOa (N-Propyl-butanoate-amine): Another one active in mice, similar properties to the others with respect to duration. This was significantly less potent than ketamine, just like the -PPOa moiety. It can then be presumed that an alkane chain extending too far past that oxygen will kill potency and activity. [17].

-iPBOa (N-Isopropyl-butanoate-amine): Another one active in mice, similar properties to the others with respect to duration. This was a bit less potent than ketamine [17] [15].

-MPeOa (N-Methyl-pentanoate-amine): I’m typically averse to building something longer than a butyl chain but other workers have determined that you still get activity with something as big as a pentanoate. This compound was a bit les potent than ketamine [17][15].

-EPeOa (N-Ethyl-pentanoate-amine): Another one active in mice, similar properties to the others with respect to duration. This was a bit less potent than ketamine [17]

-PPeOa (N-Propyl-pentanoate-amine): Another one active in mice, similar properties to the others with respect to duration. This was a good bit less potent than ketamine [17]. Interestingly though, it didn’t see as deep a drop in potency as other propyl esters did.

-iPPeOa (N-Isopropyl-pentanoate-amine): Another one active in mice, similar properties to the others with respect to duration. This was a bit less potent than ketamine [17]

Thioalkyl Chains:

This is purely hypothetical territory. As far as I know, a thioalkylamine on an arylcyclohexylamine has never been attempted. I’m just assuming that this series of compounds would have similar properties to the ethers in terms of what variations are available. My reasoning for which of these I think would be most likely to have activity is based on my reasoning for determining the activity of ethers. Once again, pure conjecture, not scientific at all.

-MTMA (N-Methyl-Methylthioamine): See series description.

-ETMA (N-Ethyl-Methylthioamine): See series description.

-PTMA (N-Propyl-Methylthioamine): See series description.

-iPTMA (N-Isopropyl-Methylthioamine): See series description.

-MTEA (N-Methyl-Ethylthioamine): See series description.

-ETEA (N-Ethyl-Ethylthioamine): See series description.

-PTEA (N-Propyl-Ethylthioamine): See series description.

-iPTEA (N-Isopropyl-Ethylthioamine): See series description.

-MTPA (N-Methyl-Propylthioamine): See series description.

-ETPA (N-Ethyl-Propylthioamine): See series description.

-PTPA (N-Propyl-Propylthioamine): See series description.

-iPTPA (N-Isopropyl-Propylthioamine): See series description.

Tertiary Alkane Amines:

Tertiary amines, as stated before, see some sort of carbon bonded to every available bond they have. This creates dialkylamines, which may perhaps be recognizable as the pattern of alterations seen in the tryptamine family of psychedelics. This has no real relation, they’re entirely different classes of drug, but its an example of how to develop that particular structure. I only go so far as propyl and isopropyl groups- it is likely that butylamines would retain some sort of activity, but there were simply too many permutations and combinations of butylamines to list out here. To get an idea of what options are at our disposal you can look at this post here.

There is evidence that suggests that the tertiary amines aren’t active chemicals themselves, but rather serve as prodrugs for corresponding secondary alkane amines [36]. This has so far been demonstrated with PCDE, which was metabolized into PCE [36]. Thus I would presume something like a PCMiP would split into some proportion of both PCM and PCiP. That is pure conjecture for now though. It is also unknown for now how a tertiary amine moiety would interact with other substitutions.

-DMA (Dimethylamine): This has been presented as PCDMA, a compound that has been demonstrated as being active in mice [17]. On the hypothesis that it would be metabolized to a secondary amine, this may very well be a prodrug to PCM, an interesting prospect. It was a little less potent than ketamine.

It should be noted that tertiary amines with esters on side will be inactive if the other side has an alkane. Eg, an arylcyclohexylamine with a methyl group and a propanoate on the nitrogen would be inactive [12]. It is unknown if this is a function of bulk or the unique metabolic properties of the ester.

-EM (Ethylmethylamine): This has not been attempted yet but I see no reason it wouldn’t be active or a prodrug for an active compound.

-DE (Diethylamine): Another compound with demonstrated activity in mice. In PCDE form it is also known as Dieticyclidine. In rats it appeared to metabolize into PCE, though it also seemed to have a synergistic effect on its own [36]. It was included in a suite of drugs published in an analytical paper intended for forensic investigation in 1982, suggesting that it was known about at the time and had the potential to be abused [21]. It would be very interesting to see more work on this.

-EP (Ethylpropylamine): This has not been attempted yet but I see no reason it wouldn’t be active or a prodrug for an active compound.

-DP (Dipropylamine): This has not been attempted yet but I see no reason it wouldn’t be active or a prodrug for an active compound.

-MiP (Methylisopropylamine): This has not been attempted yet but I see no reason it wouldn’t be active or a prodrug for an active compound.

-EiP (Ethylisopropylamine): This has not been attempted yet but I see no reason it wouldn’t be active or a prodrug for an active compound.

-PiP (Propylisopropylamine): This has not been attempted yet but I see no reason it wouldn’t be active or a prodrug for an active compound.

-DiP (Diisopropylamine): This has not been attempted yet but I see no reason it wouldn’t be active or a prodrug for an active compound.

-MCp (Methylcyclopropylamine): It is not yet known whether a cyclopropane group would retain activity on the amine of a nitrogen, but if it did it could probably function alongside a methyl group.

-ECp (Ethylcyclopropylamine): Same as the last, this may have a lower chance of being active or feasible though due to steric interference from the (slightly) larger ethyl group. But maybe that isn’t a factor. Someone who understands this better than me would know.

Allyl Chains (Secondary and Tertiary):

An enamine would be inactive but you can move that double bond just a little further down the chain to get an allyl group, which has been found to retain activity in mice in various iterations [20]. I would make a conjecture that but-3-enyl groups would also retain activity, but there is as of now no evidence to suggest that and the allyl groups are poorly understood as it stands. Perhaps that idea will come along later.

-AL (N-Allylamine): This was demonstrated to be active in vitro and in mice [20]. It had a slightly lower potency than PCP, but was more potent than any tertiary allyl amines that were attempted.

-MAL (Methylallylamine): Also active in mice per [20], and less potent than PCP. If the tertiary amine prodrug hypothesis holds, this may metabolize into PCAL and PCM.

-EAL (Ethylallylamine): Also active in mice per [20], and less potent than PCP. If the tertiary amine prodrug hypothesis holds, this may metabolize into PCAL and PCE.

-PAL (Propylallylamine): This has not been attempted yet but based on the other active allylamines I can see no reason it wouldn’t work.

-iPAL (Isopropylallylamine): This has not been attempted yet but based on the other active allylamines I can see no reason it wouldn’t work.

-DAL (Diallylamine): Also active in mice per [20], and less potent than PCP. If the tertiary amine prodrug hypothesis holds, this may metabolize into PCAL.

Tertiary Heterocyclic Amine Rings:

-Py (Pyrollidine): This is structure that has gotten itself into some hot water and has been studied a bit despite its obscurity. It is seen in the compound PCPy, or Rolicyclidine, and its limited presence as a street drug landed it as a schedule 1 substance, illegal to possess or produce in almost any context. The effects of PCPy are described as being less stimulating than PCP, with lower potency. It would be an otherwise exciting potential structure to work with- perhaps a 3-MeO or 3-HO substitution would be fruitful. There is also a possibility of strapping substitutions to the pyrrolidine ring, only one example of which I could find in literature, an old lit review from 1981 by Asher Kalir, which had a vague mention of some sort of activity in a 3”-Methyl-ethyl substituted version of PCPy [19].

-Oz (Oxazolane): Purely hypothetical- I don’t see how this would break any of the rules for an active compound however. Ether Moieties are demonstrably active as NMDA antagonists, the carbons adjacent to the nitrogen are fully saturated, and the oxygen wouldn’t alter the size and shape of the 5 member heterocycle much more than the confirmed active Pyrrollidine. I am still only going on conjecture but I think it may be worthwhile to investigate. But also Oxazolane moieties are fairly uncommon, who knows.

-P (Piperidine): This is it, this is the main one, this is by far the most extensively studied amine substitution in terms of analogue development and structure activity relationships. It is best known in the infamous street drug and the king of arylcyclohexylamines, PCP. Its reputation as a street drug aside, the non-opioid analgesic properties of PCP, its psychotomimetic effects and its high potency has fascinated researchers for decades, who have tried a massive variety of slight variations on the structure to try and identify and draw out certain desired effects. I won’t even list all the sources here that work with some variation of PCP, there are simply too many. It is the gold standard for arylcyclohexylamine research and is the standard control for comparing novel analogues to. Slight substitutions, like the addition of a 3-MeO or 3-HO group have yielded exciting substances that have seen massive appeal on the grey market. Adder fanned out to many variations on the PCP theme in his legendary bluelight thread [33], where he discovered that things like a 2’-Oxo or 4’-Oxo group supposedly turn it into an opioid. You can throw a dart at a study in the sources and further reading and you have probably a 50% of finding something with a novel PCP analogue- many attempts were made to add substitutions directly to the piperidine ring, which often retained activity- in some cases extremely bulky esters were bonded to the same site as another alkane on the piperidine and activity was retained [9]. This suggests a truly dizzying amount of possible variations on this familiar drug and so many different novel experiences it can provide.

-Mo (Morpholine): This is seen in the base compound PCMo, of which 3-substituted analogues have been attempted. PCMo is less potent than PCP. 3-MeO-PCMo was the most popular iteration of PCMo to hit the market, and it would follow that other substitutions would yield similarly promising results.

-TMo (Thiomorpholine): No such thing has ever been attempted, but I conjecture it could retain activity in the structural similarity a thiomorpholine would have to a regular morpholine.

-Pz (Piperazine): This has not been attempted, however a piperazine placed into a secondary amine is active, so long as some kind of substitution is placed on the open end of the other nitrogen, the simplest being a methyl [8]. I wonder if that activity would be conserved in a tertiary amine? We don’t know until we try!

Secondary Amine Cycloalkanes

No member of this series has ever been attempted. The premise is quite simple- just attach a cycloalkane directly to the nitrogen. Because I really have no points of reference it is for now impossible to say whether this will achieve any of the desired effects. If they did, I would venture to guess that the potency/likelihood of activity would decrease as the ring grew larger. You could possibly add additional substitutions to the rings also. Not sure how that would affect activity. I don’t know, there really isn’t much to say on any individua iteration of this series they’re all as hypothetical as the last.

-cP (N-Cyclopropylamine): This is in my opinion, the analogue most likely to be active. Small and simple. I don’t know if it could accommodate additional substitutions.

-cBu (N-Cyclobutylamine): See series description.

-cPe (N-Cyclopentylamine): See series description.

-cH (N-Cyclohexylamine): See series description.

Secondary Amine Heterocyclic Amine Rings:

Here’s where we start to get big. These are extremely bulky substitutions, but certain iterations have shown to be active in vitro, which compels me to search their possibilities more. These rather extreme variations on this theme set boundaries at either end of the possible options in terms of molecular bulk. I hypothesize that the structures with a bulk that lies between those bounds will show some degree of activity too. With a lengthening chain between the cycloalkane and nitrogen I leave out the amine rings that haven’t even been tested as tertiary amines yet.

-APy (N-Pyrollidinylamine): I have nothing to indicate this would be active, but I guess I’m going on the fact that a pyrrolidine is active as a tertiary amine, and secondary amine-amine ring moieties are active in vitro, so that’s two bits of support for possibly investigating this moiety.

-AOz (N-Oxazolanylamine): I have even less to go on with this one, as we don’t yet even know if an oxazole is active as a tertiary amine, much less with this lesser understood SAR pattern.

-AP (N-Piperidinylamine): I have nothing to indicate this would be active also, but I once again guess I’m going on the fact that a piperidine is active (and very potent) as a tertiary amine, and secondary amine-amine ring moieties are active in vitro, so that’s again two bits of support for possibly investigating this moiety too.

-APz (N-Piperazinylamine): In the paper where this compound is produced and tested, it’s technically a methylpiperazine, with a methyl group extending from the 4” nitrogen [8]. It was produced as a ketamine analogue (2-Cl-2’-Oxo-PCAPz). I am doubtful that a piperazine with a free nitrogen would work, but who knows. So this probably comes with the caveat that you’re safer strapping some alkane to that nitrogen. It showed similar activity to regular ketamine, displaying slightly more phase 2 pain relief and slightly more motor inhibition. Maybe it’s a prodrug to regular ketamine, with that piperazine ring being cleanly clipped off. Someone who knows pharmacokinetics better could answer that maybe.

-AMo (N-Morpholinylamine): Also produced and tested in [8], this showed similar potency and properties to the methylpiperazine analogue, which in turn had similar properties to ketamine. This analogue displayed slightly less activity than ketamine.

-ATMo (N-Thiomorpholinylamine): I have even less to go on with this one, as we don’t yet even know if a Thiomorphine is active as a tertiary amine, much less with this lesser understood SAR pattern.

-MPy (N-Methylpyrollidinylamine): An ethylpyrollidinylamine was active in vitro (though not the most potent) combined with a bicycloheptane ring as the base [10](more on that later), so toning it down by one carbon may retain that activity.

-MP (N-Methylpiperidinylamine): An ethylpiperidinylamine was active in vitro (though not the most potent) combined with a bicycloheptane ring as the base [10](more on that later), so toning it down by one carbon may retain that activity.

-MPz (N-Methylpiperazinylamine): Based on the n-piperazine being somewhat active in vitro [10]. This could achieve similar results perhaps. Just a guess. This would probably also require an alkane substitution at the 4”-N.

-MMo (N-Methylmorpholylamine): This would probably be some degree of active- the base amine and ethyl derivative show varying degrees of activity and this would sit there too. But we don’t know until we try. Neither of the morpholine analogues that have been made have been as active as secondary amine piperidines or pyrrolidines though, so this may not be the most promising route to go.

-EPy (N-Ethylpyrollidinylamine): This compound was devised by Ates-Alagoz et al, and was shown to be moderately active, somewhere between PCP and ketamine in potency (as far as I can interpret the data)[10]. The caveat however- is that it was attached to a bicycloheptane ring instead of a cyclohexane in the middle. That almost certainly had some effect on its potency and activity- it is unknown what that base compound even behaves like with more familiar moieties for reference (other than with a primary amine, which was shown to be even less potent than ketamine). So this is a big maybe.

-EP (N-Ethylpiperidinylamine): Another compound devised as a moiety on a bicycloheptane ring, this was the most potent of the series that was tested [10]. As stated before, it is unknown if this moiety would retain activity attached to a regular cyclohexane ring.

-EPz (N-Ethylpiperazinylamine): Extending the piperazine ring a bit further. Who knows if this would work. This would probably also require an alkane substitution at the 4”-N.

-EMo (N-Ethylmorpholylamine): Haha this one is sad 😊 But anyways, this was another variation produced in [10], it saw fairly low affinity. I included it just to map out that pattern, it wasn’t entirely inactive, but I wouldn’t expect anything in terms of potency with this. But this is also with that bicycloheptane ring- maybe it would show more activity on a regular cyclohexane.

Aromatic Secondary/Tertiary Amine Rings:

-Bn (N-Benzylamine): A Benzyl group has been demonstrated to be active in female wistar rats with similar potency and activity to ketamine (though only derivatives with a 4”-Me or 4”-MeO substitution were attempted- it is unknown if an unsubstituted benzyl group will conserve activity [6].

-BF (N-Benzofuranylamine): Pure conjecture. Benzofurans serve as active groups in many other drugs, though of course this cannot be fully extrapolated to arylcyclohexylamines, I can still take a stab in the dark that this may be worthwhile.

-MDBn (N-Methylenedioxybenzylamine): Similar to the last moiety. A Methylenedioxy group retains moderate activity on the phenyl ring of PCMo [37]. I hypothesize it may do so elsewhere, like on a benzyl ring for example.

-Ind (Indoline): Tertiary substituted indole-like structure, in this case a 2-Indoline. This retains the carbons bonded directly to the nitrogen being saturated, which may retain activity. Worth trying in my opinion.

-AI (N-Aminoindane): Similar to the last but with a secondary amine. No reason jumps out at me that this wouldn’t work. Worth trying.

-Pyr (Pyrrole): This is an exception to the saturated adjacent carbon rule. There are always exceptions it seems. Ahmadi and his team, pioneering creative new arylcyclohexylamines, devised this as a novel derivative producing PCPyr along with 3-Me-PCPyr and later 3-MeO-PCPyr [4, 5]. Interestingly, when unsubstituted, PCPyr is barely active. Only with a substitution on the 3-position of the phenyl ring does acute analgesic activity present in mice. This opens the door perhaps to other aromatic monocyclic amines, but I don’t know enough to dare venture into that. One I would maybe suggest would be a secondary amine with a pyrrole ring attached to the nitrogen. Other phenyl substitutions might make this one shine, perhaps halogens? Though you’d likely see a steep drop in potency.

-MK-801: I made this as a joke. I highly doubt it’s active or worthwhile to explore. But who knows.

 

The Aromatic Ring (and others):

Now let’s get onto the last round of modifications- We’ve dealt with the “cyclohexyl” and the “amine” part of arylcyclohexylamines. All that’s left is that first bit, the “aryl” or a shorthand for an aromatic group. An aromatic group is a ring structure that is held in a flat planar shape, stabilized by a consistent flow of electrons around the structure. This is represented on a molecular diagram as an alternating pattern of double bonds. The best known aromatic ring is the Benzene Ring, also called a phenyl group, which is seen in a vast multitude of organic molecules. Arylcyclohexylamines are shown to retain activity with a variety of aromatic groups, although almost all of the ones that have been on the market use a phenyl ring. In addition, most market examples of substituted arylcyclohexylamines have seen those substitutions added to the phenyl ring. Substitutions are likely possible on other aromatics too, though this has been poorly explored. Furthermore, there is (very scant) evidence that you don’t even need a ring here- that other straight chain structures will also be active. Very peculiar. I will go into that obscure bit of information later. Let’s dive into some of the possibilities!

 

P- (Phenyl): By far the most common and best studied aromatic group used in arylcyclohexylamines, in fact this could be considered a sort of “default” structure, as it is often broadly assumed that an arylcyclohexylamine will have a Phenyl as its aromatic. This can take substitutions on the 2 position (as seen in Ketamine, 2-Cl-2’-Oxo-PCM), the 3 position (as seen in 3-HO-PCE, 3-HO-PCP, 3-MeO-PCE 3-MeO-PCP, 3-F-PCP, MXE (3-MeO-2’-Oxo-PCE) and many others), or the 4 position (as seen in 4-MeO-PCP). It appears that 3-position substitutions are the most effective in terms of preserving potency and yield some of the most interesting results. Known 2-position substitutions see a steep drop in potency (as in ketamine), as do 4-position substitutions [33]. There is a lot to be done here.

Bn- (Benzyl): BnCP appeared as a street drug briefly in 1989 but drew enough attention to make it into a forensics journal, where a sample from Canada was analyzed [23]. There are several assumptions I will make here- first is that BnCP is active if it was being found in samples of actively sold street drugs. Second is that it was likely sold as a substitute of PCP, which would imply that it is reasonably potent. I am not sure how substitutions would behave on a benzyl group but perhaps all the same ones that can be placed upon a phenyl could be applied there. I have to wonder about a substitution on the chain carbon of the benzyl group too- whether something like a ketone or a methyl group there would affect activity or potency. Lots to investigate here but this report gives us something to potentially work off of.

2-Pyd- (2-Pyridine): This is a substitution with a fully bonded nitrogen built into an aromatic ring. The number simply denotes the position of the nitrogen, if you consider the nitrogen to be the 1 position and assign a number to the position at which the cyclohexane would be bonded. This structure appears to be moderately active in vitro but not very potent at all, according to the one study in which it was produced and analyzed [32]. The 2-Pyd analogue would allow for potential substitutions on the 3, 4, 5 and 6 positions. Lots of possibilities there, but it is unknown if these would just shake off activity, potentiate it, interact with the nitrogen in some way? Or how it would interact with other moieties? Lots of mystery here, and maybe not the most promising route to pursue.

3-Pyd- (3-Pyridine): Same as previous but this specific iteration was never made or tested. Sees a nitrogen on the 3 position relative to the cyclohexane bond. It would be interesting to make this entire series to see how shifting the position of the nitrogen affects activity. Substitutions maybe possible on the 2, 4, 5, and 6 positions.

4-Pyd- (4-Pyridine): Same as previous but this specific iteration was never made or tested. Sees a nitrogen on the 4 position relative to the cyclohexane bond. It would be interesting to make this entire series to see how shifting the position of the nitrogen affects activity. Substitutions maybe possible on the 2 and 3 positions.

2-H-Pyr- (2-H-Pyrroline): Another pure hypothetical. I conjecture that activity is retained only when the nitrogen is fully bonded within the aromatic ring- that means with no loose hydrogen on it. This is of course- pure conjecture and could easily be proven or disproven. I would like to see someone test it out. Also a nitrogen with two bonds could perhaps be stabilized with a methyl substitution extending off of it. Not much to say on this until someone gives it a spin and compares it to other similar compounds, the best would be a regular Pyrrole ring bonded to the cyclohexane at the 2 or 3 position relative to the nitrogen, and both with or without a methyl group bonded to that nitrogen.

T- (Thiophene): Even among drug nerds, the existence of thiophene arylcyclohexylamines is back shelf obscure knowledge, but it is still probably the second best known aromatic possibility behind a phenyl. This is a 2-Thiophene to be specific. It presents some very interesting possibilities- it has so far appeared as the drug TCP, sold on the street as a substitution for PCP. TCP however, is significantly more potent. PCP is already noteworthy for its potency and its fascinating that there’s even more powerful analogues out there. Another known active compound is tiletamine (2’-Oxo-TCE). The thiophene ring offers the possibility of very potent and interesting active compounds that bear some similarity to the phenyl based structures. It is possible to attach substitutions to the thiophene ring too- numbered with regards to the S being at position 1. A 3-MeO-TCP is known to be active, per a personal correspondence, but that’s all that’s known so far. So 3-substitutions are perhaps also the way to go with these structures. One study attached a number of bulky and unwieldly moieties onto the piperidine ring of TCP, including esters and phenyl ring paired on the same carbon, which were surprisingly active, at least in delivering analgesia [9]. So it seems this structure can tolerate a lot of peculiar and bulky substitutions.

3-T- (3-Thiophene): A Thiophene is active, I see no reason for a 3-thiophene to lose that activity, but SAR is full of surprises! Especially if you aren’t the best at it like me 😊

F- (Furan): In this case a 2-Furan. I suppose if a 3-Thiophene is active a 3-Furan would be too. But we still don’t know if a furan remains active. Nonetheless, I hypothesize that it will. I can see no reason that stands out that would render it inactive. I think FCP would be a good compound to begin with.

Oz-(Oxazole): Now I am getting obscure- we don’t know if an oxazole or a similar oxazolane are active in any context with an arylcyclohexylamine. So there’s no saying if an oxazole as the aromatic would conserve activity, but I see no reason why it wouldn’t for now. Who knows. It would hypothetically accept a 3 or a 5 substitution.

iOz-(Isoxazole): Same as above. Probably just as likely to work or not work. Would accept a 4 or a 5 substitution.

Tz- (Thiazole): Even more hypothetical than the last. Worth trying but completely uncharted territory. Probably best to prioritize other developments for now.

iTz- (Isothiazole): Same as above.

ODz- (1,2,5-Oxadiazole): Same as above.

TDz- (1,2,5-Thiodiazole): Same as above.

 

Before going on, there is one last set of compounds we must discuss. These compounds have only been mentioned in a single source, a review by Asher Kalir from 1981 of phencyclidine derivatives [19]. In this report, there are a few scant mentions of straight chain moieties replacing the aromatic ring and conserving some sort of activity. These would be xCP type compounds, with a piperidine as the amine. These compounds included alkanes, alkenes, and alkynes. I leave these as a highly hypothetical footnote because this is the only source to mention them and it appears that no one else has done any work with them since then. All of the cited sources in Kalir’s review are his own work or his associate’s work and I was unable to track any of it down. The data is not the most promising in terms of activity and potency, but the loose and vague descriptions of subjective effects pique my interest: “The potency was enhanced by introducing an unsaturated bond. The propargyl derivative, when tested in monkeys produced PCP-like effects, thus suggesting a hallucinogenic property.” This is probably the most wild goose chase option of the moieties I have presented here, but I figured it was worth mentioning. The Moieties Kalir cites as active, from most to least potent were:

PrE- (Propene)>Ete- (Ethene)>Pr- (Propane)>Pry- (Propargyl)

This potency ranges from about the same as PCP (PrE) to… well…the rest showed a central potency that was only about 5% that of PCP. Yet with the Propargyl, Kalir specifically mentioned observed behavioral effects consistent with PCP. Curious. An Ethane and Butane moiety were also attempted (along with an Octane) and were either inactive or so impotent they might as well be. It appears that past a certain point larger moieties aren’t tolerated, it seems the Butane is the line. The other compounds I include are just filling in the gaps or guessing at possibilities. This is all conjecture for now.

A footnote: Conformational Constraints

There is so much you can do! One possibility is the world of conformational constraints- Many of the simper arylcyclohexylamines can have their moieties freely rotate around their bond on the central ring, allowing us to disregard stereochemistry. Others have enantiomers with various configurations, for example (R)- and (S)- Ketamine. These are often administered as racemic mixtures although one enantiomer is typically more active than the other.

With a conformational constraint however, the structure is strictly bound by some sort of structure rigidly joining the rings together, disallowing free rotation of the aromatic ring. There is still stereoisomerism in the positioning of the amine and the corresponding hydrogen on the new 2’ position bond. There are many ways that this can manifest.

The first I wrote a brief article about, which can be found here.. This features a series of obscure arylcyclohexylamines with three conjoined rings, formed by joining the 2’ position of the cyclohexane with the 2 position on the aromatic ring. Doing so with PCM yielded compounds that were highly potent and active in vitro. This was done by joining the two rings with 1 carbon (yielding a cyclopentane between the other two rings, aka PD-137889) and 2 carbons (yielding a cyclohexane between the other two rings, aka PD-138289). The authors also suggest the possibility of bridging them with an oxygen or sulfur, forming a 5-member heterocyclic ring. As mentioned before, the two tested examples of this were very potent. I think this is a worthwhile path to investigate, especially experimenting with any of the aforementioned amines, aromatics, and substitutions. Perhaps the bridging carbons between the rings could also serve as sites for substitution, increasing the possibilities several-fold. An ethyl bridge/cycloheptane ring is a possibility, as may be other heterocycles. The imagination is the limit with these possibilities until their activity is better clarified by further study.

Some ideas for a variety of Conformationally Constrained Tricyclic Structures similar to PD-137889 and PD-138289

Another way conformational constraints can manifest is through a structure that is already tricyclic- PCP. This compound, called 8A-PDHQ (I will have a separate article out about this compound eventually!), sees the cyclohexane ring bonded to the piperidine ring at two points, effectively binding those rings together end to end, in this case restricting the free rotation of the amine. It should note that the cyclohexane in this case is no longer bonded directly to the nitrogen, but rather it is bonded to another part of the piperidine ring, leaving the nitrogen with a free hydrogen. This sort of structure may only work with other tertiary ring amines. Possible substitutions can still be placed on all of the rings, but the most promising may be substitutions on the 3 position of the freely rotating phenyl ring. The alternating (-) enantiomer of 8A-PDHQ was demonstrated to be about half as potent as PCP, perhaps promising.

Some ideas for structures related to 8A-PDHQ

What to study from here?

Well there’s my reasoning behind the inclusion of everything I included in this chart. I hope it was informative! It was long. It’s a lot of information to take in. So, having gathered all that information, perhaps you’re looking for direction- Though I have no credentials and am a humble amateur I would like to offer some suggestions for what may be the most promising directions for future development.

With a running interesting in organization and systematics and classification, I am of course compelled to break down the possibilities into substances of personal interest and substances of research interest.

 

Where substances of personal interest are those that pique my curiosity as one who seeks unique experiences from arylcyclohexylamines for my own exploratory purposes. Substances of research interest are the ones that would in my opinion be the most effective at establishing reference points for possible patterns of SAR, which would further aid informed development of new compounds and more reliable prediction of the effects of certain structures and moieties. It is up to you to determine what you personally consider more relevant to your interests.

 

Substances of Personal Interest:

I will be presenting these as series of compounds. An * denotes ones I am particularly interested in sampling.

Alkanes and such + substitutions:

3-MeO-2’-Oxo-PCA (MXA), 3-MeO-PCM, 3-MeO-PCPr, 3-HO-2’-Oxo-PCiPr (HXiPr), 3-MeO-PCiPr, PCsBu, 3-MeO-PCsBu, 3-MeO-2’-Oxo-PCsBu, 3-MeO-PCAL, 3-Me-PCDMA

Here we mostly see variations on some familiar alkane backbones, primarily via substitutions. It should be known that MXE, a 3-Meo-2’-Oxo substitution on a PCE, was one of the greatest discoveries in the history of arylcyclohexylamine development and many have sought to replicate that pattern on all variety of other compounds, myself included. Call it safe or uninspired, but for the sake of those going boldly into the unknown I think it offers confidence in obtaining some degree of interesting activity. Already PCPr and PCiPr have appeared on the market only as this variation. I personally find a 3-MeO substitution to greatly enhance compounds and yield fascinating experiences. Thus I think a 3-MeO-PCM, 3-MeO-PCPr, 3-MeO-PCiPr, and 3-MeO-PCsBu are in order. Why sBu instead of Bu? Arbitrary, just my personal interests. I would like to see that backbone both on its own and with the MXE substitution pattern. The MXE substitution pattern is purported to retain interesting effects with a 3-HO instead of a 3-MeO too. 3-MeO-PCAL and 3-Me-PCDMA are purely experimental, really no way to predict what they might be like. If the prodrug hypothesis of tertiary chain amines holds up, I wonder if this would yield just 3-Me-PCM? The MXE substitution on a PCA would also be interesting in my opinion.

 

PCE variations:

3-Me-PCE, 3-Et-PCE, 3-iP-PCE, 3-EtO-PCE, 3-F-PCE, 3-TFM-pCE, 3,4-MD-PCE, 3,4-Fu-PCE (BZFCE), 3-MeT-PCE, 4’-F-PCE, 3-Me-2’-Oxo-PCE, 3-MeO-4’-PCE

The PCE base has produced some of my favorite compounds. While there is an absolutely dizzying variety of amines out there, I feel like there is so much that can be done on this comfortable and familiar base. It seems like a good consistent platform to experiment with a variety of substitutions to tease out what their individual effects may be. To that end I think it would be super interesting to see really any of these compounds. It’s all just me kinda randomly brainstorming there isn’t any specific rationale for each choice.

 (NOTE: Since the publication of this article, 3-Me-2'-Oxo-PCE has become available on the market- While I assinged it the name MeXE, the market forces and the community have already unfortunately gone with the name "DMXE", (the D for a deuteroxy or something) which ends up being fairly misleading and tosses out conventions. I hope to have a report written for it soon)

Alkoxyamine compounds:

PCHOPA, PCiPBA, 3-Me-PCiPEA, 3-Me-PCPEA

Several ether amines have already made it to market, though they have remained obscure and no information on their subjective experience exists. This is just filling in the blanks of compounds that haven’t been made yet but follow logical paths of development with ones that have. I offer a 3-Me substitution as a possible safe bet to combine with an ether amine, but in reality, I have no idea how such moieties interact.

 

Thioalkanes:

PCMTEA, PCETEA, PCPTEA, PCiPTEA

No thioalkanes have ever been attempted as the amine moiety. I have no idea if they would work or what they would feel like. I would love to find out though. These compounds may be a good place to start.

Tertiary Amine Rings:

3-Br-PCP, 3”-Br-PCP, 3”-MeO-PCP, 3-MeO-4’-Me-PCP, 3,4-Fu-PCP (BZFCP), 3,4-MD-PCP, 3-MeO-2’-Oxo-PCPy (MXPy)

Like PCE, PCP provides a tried and true familiar base from which to build interesting and exciting compounds from. It also presents a whole new ring to which substitutions can be added. There is an ocean of possibilities here. I present some miscellaneous ones that jumped out to me, along with a PCPy with the MXE substitutions.

 

Secondary Amine Rings:

PCcP, 3-MeO-PCcP, 3-MeO-2’-Oxo-PCcP, PCAPy, PCAP, 3-MeO-PCAP, PCEP, 3-MeO-PCBn, 3-MeO-2’-Oxo-PCBn (MXBn), 4-Me-PCBn, 4”-F-PCBn, 3”-MeO-PCBn, PCBF, PCMDBn

These are not understood nearly as well as the tertiary amine rings. It is known that a secondary amine aromatic ring can tolerate substitutions, per [6]. First, we look at PCcP, and the corresponding 3-MeO and MXE substitution pattern. PCcP is a real interesting possibility but there isn’t much reference for what it may be like. Such a small ring may show similarities to a chain alkane in vivo. PCAPy and PCAP also seem to provide an interesting possible substrate for activity (to understand why see their section in the moiety descriptions, I don’t feel like copying and reformatting it all). Lastly there are Benzyl groups, which according to [6] can take a substitution on the benzyl ring, so some possibilities of that are explored, along with of course, the MXE substitutions. Lastly is PCBF and PCMDBn, two polycyclic rings that could prove interesting with the benzyl group.

 

Thiophene Esters

TCEBOa, TCiPBOA

There were so many ester moieties available, I wanted to delve into them a bit. The ester amine moieties present something interesting- extremely fast and short acting compounds. This was added to a ketamine base- so how would it behave in a different context? For such a rapid experience, I suspect it may benefit from jacking up potency as much as possible- To that end I suggest a Thiophene in place of a phenyl ring, as that tends to yield greater potency. The possible moieties I chose were filling in gaps between ones that had already been produced and tested. But honestly you could take your pick from the list, there’s so many promising and interesting options. Perhaps this will be a dud, the short duration would be no fun, perhaps it would be real fascinating though, it’s hard to say with the data that exists for now.

 

Furan Compounds

FCE, FCPy, FCP

None of these have ever been tried! They seem super promising though I think it would be interesting to see an attempt made.

 

Benzyl Aromatics:

BnCE, 3-MeO-BnCE, 3-MeO-2’Oxo-BnCE, 3-MeO-BnCP, α-M-BnCP

Here are some compounds that expand on the theme of using a benzyl instead of a phenyl as the aromatic. Just working in the basic and familiar possibilities- perhaps more interesting and abstracted variations can be built on it once we figure out what these substitutions do. One variation that I don’t mention in the flow chart is the addition of an α-methyl group on the carbon between the cyclohexane and the phenyl ring in the benzyl group. What this may do is entirely unknown. Worth a shot I think! Indeed, the base structure of BnCx is very very obscure and poorly understood.

 

Substances to Research:

I’m not using “research” as a euphemism here, as it so often appears in this community. I think it would be great to see formal studies done on these sets of compounds just for the sake of characterizing them and systematically discerning clear SAR patterns. I would suggest production, characterizing, an in vitro affinity assay, and perhaps animal behavioral and analgesia tests for each series of compounds. This can help indicate specific receptor activity, potency, and toxicity. In characterizing SAR of these series, it provides us with a more robust framework for developing new compounds and reliably predicting their specific effects, and thus their therapeutic and exploratory applications and contraindications.

 

Series 1: Alkane Amine Chains

Analysis of this series would clarify a few properties of the Alkane Amine chains of arylcyclohexylamines. Namely, the correlation between chain length/configuration and potency or activity. PCP and PCPy are included as reference compounds. Performing this study would allow for more reliable prediction of what substitutions on these bases will accomplish and how they change effects in relation to amine bulk.

Series 2: Variable Substitutions on PCE

This series uses PCE as a standard- it provides a reliable base with known effects for adding substitutions, by which alterations in activity and potency can be observed. PCM would also be a reasonable base for such a study. While PCP is the gold standard, the ring structure may cause unpredictable effects in relation to substitutions. It could very well be done as a separate analysis however. This concerns only alkane chains and alkane ethers for now. I am particularly interested in seeing the correlation between substitution bulk and potency/activity.

Series 3: Thioalkane Amines

As mentioned before Thioalkanes have not been attempted yet as amine moieties. This series would help to clarify if they are active in the first place and the correlations between chain size and activity.

Series 4: Aldehyde Amines

Aldehyde amines have not been attempted either and it would be interesting to determine their activity and possible toxicity.

Series 5: Furan Aromatic Arylcyclohexylamines

Also as mentioned before, Furans as the aromatics have not yet been attempted but show promise. This is a very basic series of compounds to feel out relationships between structure and activity/potency.

Series 6: Pyridinyl Aromatic Arylcyclohexylamines

This series is to determine how the position of the nitrogen on a Pyridinyl ring as the aromatic affects potency and activity. 2-Pyd is the only one that has been manufactured so far, and it was only moderately active. Others may show other interesting effects.

 

There is little more I can do beyond this, it’s out of my hands and beyond my skillset and I pray that this information is useful enough to serve those with the ability to further study this fascinating class of compounds! Godspeed you researchers.

 

Sources and Further Reading:

[1] Ahmadi A, Khalili M, Abbassi S, Javadi M, Mahmoudi A, Hajikhani R (2009) Synthesis and study on analgesic effects of 1-[1-(4-methylphenyl) (cyclohexyl)] 4-piperidinol and 1-[1-(4-methoxyphenyl) (cyclohexyl)] 4-piperidinol as two new phencyclidine derivatives. Arzneimittelforschung. 59(4):202-6

[2] Ahmadi A, Khalili M, Mihandoust F, Barghi L (2010) Synthesis and determination of acute and chronic pain activities of 1-[1-(3-methylphenyl) (tetralyl)]piperidine as a new derivative of phencyclidine via tail immersion and formalin tests. Arzneimittelforschung 60(1):30-5

[3] Ahmadi A, Solati J, Hajikhani R, Onagh M, Javadi M (2010) Synthesis and analgesic effects of 1-[1-(2-methylphenyl)(cyclohexyl)]-3-piperidinol as a new derivative of phencyclidine in mice. Arzneimittelforschung. 60(8):492-6

[4] Ahmadi A, Solati J, Hajikhani R, Pakzad S (2011) Synthesis and analgesic effects of new pyrrole derivatives of phencyclidine in mice. Arzneimittelforschung 61(5):296-300

[5] Ahmadi A, Solati J, Hajikhani R, Pakzad S (2011) Synthesis and analgesic effects Methoxy-Pyrrole derivatives of phencyclidine in mice. Arzneimittelforschung 23(12):5429-32

[6] Ahmadi A, Khalili M, Hajikhani R, Horiesadat H, Afshin N, Nahri-Niknafs B (2012) Synthesis and study of the Analgesic effects of new analogues of ketamine on female Wistar rats. Journal of Medicinal Chemistry 8(2):246-251

[7] Ahmadi A, Khalili M, Marami S, Ghadiri A, Nahri-Niknafs B (2014) Synthesis and pain perception of new analogues of phencyclidine in NMRI male mice. Mini Rev Med Chem. 14(1):64-71

[8] Ahmadi A, Khalili M, Asadi A, Nahri-Niknafs B (2014) New morpholine and piperazine derivatives of ketamine: synthesis and anti-nociceptive effects. Bulgarian Chemical Communications 46(3):556-562

[9] al-Deeb OA (1996) New analgesics derived from the phencyclidine analogue thienylcyclidine. Arzneimittelforschung. 46(5):505-8

[10] Ates-Alagoz Z, Sun S, Wallach J, Adejare A (2011) Syntheses and pharmacological evaluations of novel N-substituted bicyclo-heptane-2-amines at N-methyl-D-aspartate receptors. Chemical Biology & Drug Design. Jul;78(1):25-32

[11] Bigge CF (1993) Structural requirements for the development of potent n-methyl-d-aspartic acid (NMDA) receptor antagonists. Biochem. Pharmacol. 45(8):1547-1561

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