MXPCP

Age: 30

Weight: 140 lbs

Dosage: 170 mg intransal

Setting: At home by myself. In a good mood.

 

[Please note: I have developed a dissociative tolerance and I also prefer strong experiences. This is a massive dose for a normal person. For someone without a tolerance I would suggest starting at 25 mg for this compound. An substantial experience for most would be found around 60-80 mg. An experience similar to mine would probably be found around 120 mg]

 

2025 has seen an explosion of development in the realm of 2’-Oxo arylcyclohexylamines, notably with O-PCPr and O-PCP (report pending). I am not sure what has stoked this flourishing of compound development but I will say that I am pleased to see it. MXPCP (frustratingly originally named MXP, which is already in use) comes in with 2 modifications that are tried and true- the 3-Methoxy substitution that has given us so many fruitful compounds like 3-MeO-PCP (or MXE) and the N-piperidine, for PCP. Unlike O-PCP, this has never been synthesized before or tested in any context, though it has often been theorized about. Since the synthesis of 2’-oxo substituted PCP compounds was cracked it was really only a matter of time before that was mixed and matched with some of the winning phenyl substitutions. I was nonetheless surprised to see this- just looking at the molecule there is an apparent potential issue with sterics as far as these large substitutions are concerned- O-PCP was already a challenge with synthesis that was miraculously solved- strapping even more onto that molecule that could bump into those two existing groups seemed like a fantasy but it appears to have played out right before our eyes! This opens the door to so much development, ideas that I’m sure are already on deck for the labs producing these- 2-F-2’-Oxo-PCP, 2-Cl-2’-Oxo-PCP, 3-F-2’-Oxo-PCP, and 3-Me-2’-Oxo-PCP are all things we can expect on the horizon as the market optimizes itself along the lines of observed in vivo SAR. As we’ve never had a 2’-oxo phenyl substituted PCP compound before, this is literally illuminating a new area of the map for structure activity relations. It is a relation of modifications we really have never seen before but it shows promise for development of other compounds in a similar direction!

In terms of effects, this is perhaps the ultimate party drug. There is an appreciable initial rush with a lot of energy and stimulation but still a bit of that 2’-Oxo dissociative heaviness like ketamine that makes it feel floppy and fun to dance. There’s an electric tension and energy that pulses through my veins, there is almost a sense that I am projecting into an glowing avatar of myself that can function and navigate the world as an idol of pleasure and energy and hedony. There is an urgent euphoria that wants to explode out onto the rest of the world, the kind that would delight in loud noises and bright flashes. This drug is felt through the body as pulses, raging ripples of light that crackle with synesthesia- I haven’t experienced it in the context of being battered by high intensity sound waves but I can imagine they would harmonize perfectly. Most users will find a pleasant short lasting heavy dissociative stimulation at 20-30 mg. Turning the dose up increases the “heaviness” but only to a point- after about 80 mg or so (~100 mg for me) the only quality that increases is the stimulation, tension, and mania. The rush is intense with every redose. I chased this one to a high dose in search of a hole but it doesn’t seem possible with this compound- as stated before the heaviness and depth plateaus out and only the stimulation increases after a point. It doesn’t have any kind of insightful or introspective headspace in the lingering comedown like most manic dissociatives though, it is rather shallow in that regard. Not the sort of compound for late night solitary meditation or meaningful introspection. But it has its place as something fun for settings where not much thinking is required- a perfect “shut up and dance” drug in my opinion.

 

T0:00- Small crystals are easily crushed into a fine powder. Dose administered intranasally. Stings a little but it’s completely manageable. Powdery bitter taste.

 

T0:15- Onset, feeling a little lightheaded.

 

T0:20- The lightheadedness increases, feeling a bit more jittery and tense.

 

T0:25- The dizzying rush hits harder and harder. I am feeling more uncoordinated in my extremities. An intense stimulation is coming in under everything, chasing through my limbs and to my fingertips.

 

T0:30- It’s accelerating now, in a way that makes me grip my knuckles with wind whipping through my hair. This is a tight, tense dissociation, like my essence is being pulled and stretched taught from the back of my skull, leaving my fingers to tap my keyboard in staccato plunges; like I am being constricted and pulled tight but with this rush of pleasure like a tightly braided riffle in a rapid clear steam. My fingertips feel cold and numb, yet a pervasive electric warmth radiates through my body. If I don’t give them my attention, my extremities all but fall away into a buzzing dissociative void like a leaf being torn away by a current.

I have been watching various YouTube videos- first person combat footage, playthroughs of boss fights from games I will never play- I am drawn to the rapidity and flash of the content but little else beyond it. My brain is mostly lucid but now shocked into a state of seeking things purely at the level of the sensory stimulation they provide. It is becoming harder to read the words on my screen, my visual field is being split in two, blurring everything as faint visuals begin to stream in from the sides as tightly binding ribbons of flashing small concentric patterns.

 

T0:40 – What a rush! I feel chills running down my limbs pulling me taut. Pleasurable shocks of electric streamers buzzing down the bones and nerves of my limbs. I smoke some cannabis. This odd interplay of hot and cold is rushing and swirling together to increasingly greater heights- it will  be a chill down my spine and across my ribs like the electric arcs of a Jacob’s ladder, the cold numbness in my extremities like I have been holding my hands and feet in the rush of a cold mountain stream, but a definite warmth crawling over my vertebrae like the long tongues of flames licking and tracing their way up the limbs of a tree they want to consume to white caustic ash. My muscles feel sprung back and ready to launch. How I would love to just get up and dance right now! The visuals increase in depth and contrast, in rusty colors of red and orange, bright and tense and roaring across my visual field like clattering subway cars, tracing the forms of any stark lines or bars I see in my vision.  A dissociative sinking heaviness has set in too, a pouring, rushing, draining from the top of my skull down across the rest of me. There is also a heavy numbness and floppiness to this.

I feel driven, but it is quite unlike the drive and stimulation I feel from other manic dissociatives. I am shocked to realize my heart is beating only a bit faster than normal, not pounding at my ribcage as I had suspected. It feels like I am crashing over into the realm of explosive anticipation and excitement and it is curious to me that my body has not objectively come to meet that sensation.

There are pushes of mania here in a purely social sense as in “I should talk to xyz person, right here, right now” but little actual compulsion towards anything meaningful to say or share. It is like the energy of mania without any of the underlying drive of self-actualization, a façade of the manic state without the structure- empty boxcars just raging endlessly forward with all the clatter and decorum but hardly even a vagabond oogle camped out within. For most other substances I would consider manic, there is a drive to generate and pursue ideas, ideas that feel deeply fundamentally correct without any real basis. Here, there is that same sense of drive, just without the ideas or schemes for that drive to latch onto. All the trappings and signifiers and emblems of the manic state without the actual force and direction. But this is pleasant still, and that unfocused, un-fleshed out energy can still be directed into physicality, into moving, dancing, into those deeper and primordial fundaments of how a human can expend its respiration, it doesn’t need to be that deep.

 

T1:00- Although I feel so tense and jittery, I try to submit to the experience, because there is certainly some of that dissociative weight present, the kind of heft that would lead me to think there is a hole to be found here. If I sit still I am beset by a numbing heaviness and a drawing away of the physical perception of my limbs that suggests that there is a sort of all-encompassing dissociative hole experience to be found here. I plug in my headphones try to listen to something with high energy that I hope will match the drive of this pulsing raging drug. In this instance it is Femtanyl’s album “Reactor”. I ultimately do not find myself engaged in this space for very long- despite its perceived heaviness, this is not a drug that lends itself to an all-consuming hole. The closed eyed space is bright, taken with the same warm-colored visuals of pulsing and streaming and flashing lines. There is some flowing synesthesia and a sense of blossoming and exponentially growing patterns and forms, but they are 2-dimensional and devoid of fine detail. I am fully aware of my body and its presence with my eyes closed, despite some depletion of sensation, it is hard for me to ignore my bones and the idea that they are real and present and that I am real and present. No fully immersive fantasy to be found here.

I give up and recover and reenter the real world and bask in the heat waves of the continual hot dissociative rush, my vision still ragingly blurry, my body content to be still in the buzzing heft. And indeed if I get up and move I am only slightly uncoordinated, I can still get about without crashing into things or stumbling  around. There is simply too much going  on for me to sink into a hole. At least physically- there is admittedly not much going on in my head, just a blankness reveling in these pulsing rushes. I feel like I am being cooked, something bitter and bright, screaming and raging like a bomb of dissociative pleasure.

 

T1:30- Getting up and moving around makes it feel like I am a projected glowing vitreous avatar of myself- a form that is sexier and more muscular than my own, built of uniformly clear colored glass. A great tense idealized titan that can dance and thrust and punch and beam into the sky without really having to think too much.

There are many dissociatives I would describe as insightful, where I am driven to pursue and consume and process information, as much as possible as quickly as possible. I tend to feel this sensation at the front of my brain with a burning behind my eyes as if they are glowing furnaces ready to take in and metabolize whatever the world around me has to offer. This turns to compulsions to read or learn or engage with media. This normally intertwines perfectly with sensations of mania and stimulated dissociative lucidity. For this compound however, this is oddly absent- the stimulation and energy and drive are there, but there’s no one behind the wheel, no particular compulsion to engage with information, and an odd sort of inhibition in place of lucidity. It feels like an aggressively enforced hollowness, like an eager energetic dog with a completely blank expression.

Visuals still persist strongly as beads and lace strung and cast across my vision.

 

T2:00- Starting to feel a distinct and smooth comedown, with less tension in my limbs and fingers and less of a rushing sensation.

 

T2:40- I play the videogame “Shadow of the Colossus” now and find that there isn’t any degree of inhibition to my fine motor skills or cognitive processing at this point that would interfere with the game. Still a similarly smooth comedown with some tense lightheadedness and lingering stimulation. I am probably lacking something in receiving the brilliant artistry of this game in this state.

 

T3:20- I feed and mist all of my pet arachnids (10 tarantulas, 2 amblypyids, 1 vinegaroon and a jumping spider), a task that also requires some degree of motor skills, and notice no issue or interference at all. Most of the tension has died down, there is just a lingering burning lightheadedness and numbness still.  

 

T4:00- Mostly back to baseline, feeling stimulated and still a little numb in my toes and fingertips.

 

T5:00- Feel entirely back to baseline, try to sleep. Sleep came with difficulty even with my normal prescribed sleeping medications (50 mg trazodone) and I woke up a few times throughout the night too. Felt groggy and fatigued the whole next day.

 

Conclusion: This would make for an excellent party drug, and perhaps not the kind of party where one is having engrossing conversations either, but the kind with bright lights and loud noises and lots of dancing. This drug is highly euphoric with a powerful rush, but most of its properties lie in physicality. It is one of the most physically pleasant dissociatives I have tried and perhaps one of the most hedonistic ones, but it offers little in term of insight or introspection. The short duration and decent potency but forgiving nature in terms of dosing higher all go to serve casual use in the dark. I find it doesn’t really add much when combined with other dissociatives beyond a rush and some visual flare. There is a decent weight to it that makes it floppy and fun to dance with,  but the stimulation doesn’t allow for an all-encompassing hole. Effects plateau out at and higher doses really only increase the stimulation and muscle tension. There is something resembling mania but without any kind of depth or coherency that produces the kind of results that manic states can bring. One can find themselves mostly in control of their body and mind for the most part, though there is a good degree of cognitive inhibition. It is dumb, colorful fun, but a great deal of it at that.

Abelian 2024: An analysis of the structure activity relations of 24 2'-Oxo substituted Arycyclohexylamines (Ketamine, MXE, O-PCE, etc. )

 The full text can be found here:

https://ui.adsabs.harvard.edu/abs/2024PhDT........40A/abstract

 

Tl;dr: We now know how different nitrogen substitutions affect the activity of ketamine and MXE analogues. PCE analogues have the highest affinity, and pairing a 3-Methoxy with the 2’-Oxo substitution also offers us high affinity, so it probably makes sense to continue developing compounds along that pattern (though there really isn’t much left to explore at this point). One really interesting thing that stood out is that an N-cyclobutyl substitution has decently high affinity! This is definitely something that should be explored more.

 

Another fantastic and comprehensive paper has come from a friend and former colleague, the wonderful Dr. Anush Abelian! In her PhD dissertation she sets out to synthesize and analyze a series known as the β-Ketoarylcyclohexylamines- This means arylcyclohexylamines that have the 2’-Oxo group, also labeled as a β-Ketone. This substitution lends unique subjective properties to the dissociative experience- compounds with the β-Ketone often feel heavier, more hole-y and sedating compared to the manic and stimulating phenyl-substituted base arylcyclohexylamines. They tend to be less potent, which makes doses more forgiving for casual use. They tend to have shorter durations. Perhaps the most famous dissociative of all contains the β-Ketone structure: Ketamine, which could also be labeled as 2-Cl-2’-Oxo-PCM.

The observation of the unique effects of ketamine inspired further development along the lines of compounds containing both the 2-Oxo substitution paired with various aryl substitutions. In research for example, Sleigh et al. 2015 and Jose et al. 2013 delve into various long reverse ester chains on the secondary amine for very short acting ketamine analogues. Tiletamine, which contains a thiophene instead of a phenyl ring (+ an ethylamine, could be written as 2’-Oxo-ThCE, or ThXE using drug nomenclature), was developed as a veterinary anesthetic.

Primarily though, development of novel compounds and data on the in-vivo activity of these drugs has been driven by the grey area research chemical market and community. Fastanbulbous on Bluelight developed MXE based on hypotheses about SAR and started a revolution with arylcyclohexylamine development. Many compounds followed suit after MXE’s extinction, using the same _X_ naming convention to capitalize on the Hype- like MXM, MXPr, MXiPr, 2-FXE. (Even unrelated diarylethylamines got caught up in the hype: MXP). Others were developed as base β-Ketones with no phenyl substitutions, like DCK and O-PCE, both of which proved to be worthy and interesting compounds. Various analogues directly inspired by ketamine appeared on the market too, like 2-F-DCK, 2-Br-DCK. Needless to say, this is a really exciting area of drug development and there is so much potential for so many unique and interesting compounds!

Dr. Abelian has for the first time done a comparative analysis of an entire series of these compounds, detailing their synthesis, comparing their binding affinities and projected pKa’s and laying out a map for the structure-activity relations of the entire family of compounds along with potential future compounds!

Her findings are multitudinous and the inclusion of more experimental compounds helps expand the potential for future developments.

The following paragraph is all chem synth skip it if that’s not of interest.

The synthesis of each compound is laid out clearly! For the chem folks, it’s a classic modified Calvin Stevens ketamine synthesis with a ring rearrangement starting with a substituted phenylcyclopentyl ketone (Stevens et al 1966). This can be formed from reacting a cyclopentane Grignard with the corresponding benzonitrile. The starting unsubstituted and 2-Cl substituted phenylcyclopentyl ketone were inexpensive and readily available for laboratory purposes (I’ll never forget that odd sickening strong celery smell that seemed impossible to wash off of anything…) so the Grignard step was usually unnecessary. The ketone is then brominated at the α position with aluminum chloride and bromine, which can then be converted into the α-hydroxyketone via reacting it with a strong base. With that, a light-sensitive imine is formed by reacting with the corresponding alkylamine, which then undergoes a rearrangement under microwave radiation, yielding the final β-ketoarylcyclohexylamine. All reactions were done under argon and all products were purified by column, then formed into the HCl salt by the addition of a molar equivalent of HCl. Further purification by recrystallization yielded excellent product! It should be noted that with the 2-Chloro substituted compounds, microwave radiation yielded a highly fluorescent byproduct. In those cases, the bromine intermediate was reacted with 6 equivalences of base to yield the α-2-chlorophenyl-hydroxycyclohexylketone. This was aminated by reacting it with Methanesulfonyl chloride, followed by the corresponding alkylamine. Each compound is extensively analyzed and characterized, which can be used as reference for drug testing programs.

For the pharmacology and structure activity relations nerds, we look at table 3.1, which lays out the binding affinities for the entire series of compounds:

 

 

A lot of really interesting observations we can make from this beautiful data! A lot of patterns we can draw! Let’s look at the different  categories of compounds. Here are the affinities displayed visually with the molecules in order from highest affinity to lowest affinity. It’s important to remember that a lower number signifies higher affinity.

 

But……….
First we gotta talk about nomenclature! We need to lay this out and communicate this clearly!  How we name these things- it's confusing! There’s the scientific way of naming things, and there’s the market way of naming things. As I discuss these compounds I will follow the naming conventions listed below.

 

There is the substituted xCx naming convention for arylcylohexylamines. You list the substitutions, and then the base structure. The first x is the aromatic ring, almost always a phenyl ring, P,  the C is the cyclohexyl ring, the last x denotes the amine, always changing, which is the object of interest here. It yields us things like 3-MeO-PCiPr etc.

 By this scheme ketamine would be listed as 2-Cl-2’-Oxo-PCM.

Then MXE came out, everything wanted to be like MXE! Our naming conventions got fucked. Now we use the MXE denotation of MXPr, MXiPr, FXE, DMXE etc. Gotta ride the hype! The way this nomenclature is structured is: 2’-Oxo compounds with a substitution of any kind on the phenyl ring get the xXx label, The first character being the corresponding phenyl substitution, (F for Fluorine in FXE for example, M for 3-Methoxy, DM for methyl (“desoxy”), H for hydroxy (as in HXE); a 3- position substitution is assumed and if that is not the case, the number substitution is affixed to the front, as in 2-FXE), the last character corresponding to the amine. By previous convention, MXE is 3-MeO-2’-Oxo-PCE. The capital X in the middle represents the 2’-Oxo group in this nomenclatural structure.

Lastly, there are the compounds with no aromatic substitutions- the most popular ones are DCK and O-PCE, which seem to follow no rhyme or reason. I hate this shit! We should have a system and a standard. O-PCx. I think this is fine nomenclature. DCK should technically be called O-PCM. But I will use this convention for these compounds, just for ease of writing.

So we end up with these naming schemes. Things have been called names like n-ethylnorketamine which make things more confusing! We just name things in relation to other things. That aforementioned compound is 2-Cl-2’-Oxo-PCE! You could call it ClXE (if a chlorine is involved it seems everyone just calls it ketamine!). I think the easiest name for that compound is probably just ethylketamine though. Having 3 different naming schemes depending on the substitutions the drug has is not a good way to do things, it breeds confusion and misunderstanding and obscures the patterns of relations between these compounds. But that is where we are and we’re just kinda stuck with it.

 

Anyways,

 

 

Let’s look at the patterns and structure activity relations!

 

Start with the unsubstituted 2’-Oxo-compounds: These are the ones that can fall under the nomenclature of O-PCx. They have beta ketone on the cyclohexane as ketamine and every compound in this study have. These ones have no substitution on the aromatic ring. These are familiar compounds: DCK, O-PCE. The ones listed in this study are:

O-PCA (2’-Oxo-PCA)

O-PCM (2’-Oxo-PCM, Deschloroketamine, DCK)

O-PCE (2’-Oxo-PCE)

O-PCPr (2’-Oxo-PCPr)

O-PCiPr (2’-Oxo-PCiPr)

O-PCEtOH (2’-Oxo-PCEtOH)

O-PCAl (2’-Oxo-PCAl)

O-PCcP (2’-Oxo-PCcP)

This affords us a really interesting view of the effect of different amines in 2’-Oxo substituted ACH receptor affinity. They are in order of affinity- O-PCE> O-PCiPr>O-PCM> O-PCPr>O-PCAl>O-PCA>O-PCcP>O-PCEtOH- this seems to map pretty predictably and reliably on in-vivo potency and also mostly follow the pattern seen in non 2’-Oxo subbed ACHs: O-PCE is quite potent, O-PCM (DCK) a little less so, and O-PCPr less so than that. One could predict that the potency of O-PCiPr would fall between that of DCK and O-PCPr. The more exotic amine substitutions didn’t show a higher affinity than ketamine, so would expectedly be less potent than it, though this says nothing about the actual qualitative experience. O-PCcP would be pretty impotent though and would require the ingestion of a large amount of powder. O-PCEtOH has such a low affinity one would presume it bordesr on potentially being inactive. However, two active compounds with this substitution have been observed: First with a ketamine analogue (That would be 2-Cl-2’-Oxo-PCEtOH) where this compound was actually the most potent of a series of ketamine esters and ethers (Jose et al. 2013). An unsubstituted version of this compound was also allegedly sold on the market and was supposedly active in-vivo though there is no detailed information on the effects (Morris Wallach 2014). It is entirely possible for an arylcyclohexylamine to have very low affinity but still be appreciably active in vivo- this is seen in 3F-PCP, where affinity would indicate it is wholly inactive, when this clearly isn’t the case (Wallach 2014). It appears that there is a sweet spot with the ethylamine for highest affinity, and that affinity is conserved by keeping to roughly that size and shape (hence why isopropyl shows higher affinity than propyl).

 

From there we can compare the next category of compounds- non halogenated phenyl substitutions-The MX style compounds

MXM (3- MeO-2’-Oxo-PCMe)

MXE (3-MeO-2’Oxo-PCE)

MXPr (3-MeO-2’-Oxo-PCPr)

MXiPr (3-MeO-2’-Oxo-PCiPr)

DMXE (3-Me-2’-Oxo-PCE)

DMXM (3-Me-2’-Oxo-PCM)

In order of affinity: MXiPr>MXPr>MXE>MXM>DMXE>DMXM. This is an interesting case in affinity not correlating to in vivo potency- any seasoned dissonaut can tell you that MXPr and MXiPr were not at all more potent than MXE. I cannot begin to imagine what the reason for this discrepancy is, but it’s an important lesson in not really knowing what a drug does until you try it. I am curious if this pattern of affinity just increasing with larger carbon chains on the amine holds true for this particular substitution pattern- does it then hold true for 3-HO substitutions? What about a 3,4-MD substitution? It all remains to be seen. Most of these compounds have been made and tested in people so this data is more just curious for how it doesn’t align with in-vivo activity than predictive or anything.

 

Then we look at the compounds directly adjacent to ketamine. I don’t really know what to call these.

We have:

Norketamine (2-Cl-2’-Oxo-PCA)

Ketamine (2-Cl-2’-Oxo-PCM)

Ethylketamine (2-Cl-2’-Oxo-PCE, N-Ethylnorketamine)

Propylketamine (2-Cl-2’-Oxo-PCPr, N-Propylnorketamine)

Cyclopropylketamine (2-Cl-2’-Oxo-PCcP, N-Cyclopropylnorketamine)

Allylketamine (2-Cl-2’-Oxo-PCAl, N-Allylnorketamine)

Cyclobutylketmaine (2-Cl-2’-Oxo-PCcBu, N-Cyclobutylnorketamine)

For these compounds, we have in order of affinity: Ethylketamine> Cyclobutylketamine >Ketamine>Propylketamine> >Norketamine>Allylketamine>Cyclopropylketamine. These compounds seem to follow the pattern laid out by the normal 2’-Oxo substituted compounds. Interestingly it seems at the very least the 2-halogen position doesn’t run into the odd pattern seen with the 3-alkane or alkoxy substituted compounds. I don’t know if this is a function of the 2 position or a function of the substitution being a halogen. Other structures would have to be tested to elucidate any pattern, like a series of 3F or 3Cl substituted compounds, or a series of 2-MeO substituted compounds. Interestingly, cyclobutylketamine has a higher affinity than normal ketamine! I wonder if this property extends to other substitutions with the cyclobutylamine- or why this seems to go against the trend of bulkier chains losing affinity- would be super curious to compare to straight chain butyl or other butylamine isomers, particularly sec-butyl. This shows a lot of promise in developing new compounds with this amine. In correspondence with Dr. Abelian, she suggested this discrepancy is because the binding pose of ketamine at the PCP site within the NMDA channel is unstable, shifting between 2 different conformations that bind to 2 different parts of the binding site (Zhang et al. 2021). It is not yet known what may modulate one conformation over the other or if it’s seemingly totally random, but either way this could potentially result in SAR discrepancies

 

Lastly, there are 3 tertiary amines with 2 alkane chains:

Dimethylketamine (2-Cl-2’-Oxo-PCDMe)

Methylethylketamine (2-Cl-2’-Oxo-PCMeE)

Methylpropylketamine (2-Cl-2’-Oxo-PCMePr)

These in rank order of affinity are Methylethyl>Methylpropyl>Dimethyl. These have not been explored really, it is theorized that aryclcyclohexylamines with tertiary dialkene substitutions are metabolized into 2 sets of the corresponding secondary amines (Cho et al. 1993). It is not known if this is also seen when there are 2’-Oxo substitutions- it is also likely that these compounds are active in their own right when they are not metabolized, though it is possible that the fate of them in vivo is to always be metabolized into those 2 secondary amines.

Is there anything else to look at?

One last pattern to analyze is the relations across the different ring substitutions? We can in 2 cases compare the 2’-Oxo cyclohexane substituted ACH’s across 4 aromatic substitution patterns: Unsubstituted, 3-Methyl, 3-Methoxy, and 2-Chloro. We have this dataset for PCM and PCE. For both compounds, affinity is greatest along the following pattern: Unsubstituted>3-Methoxy>2-Chloro>3-Methyl. I would be curious to see where 3-halogenated substitutions would fall on this pattern- interestingly, 3-Methyl substitutions are higher affinity for non 2’-Oxo substituted ACH’s- they seem to drop off here though. Just goes to show that MXE was a really brilliant design!

 

Conclusion, tl;dr, going forward:
So now we have a really nice map of the structure-activity relations of 2’-Oxo substituted compounds. The 2’-Oxo substitution grants arylcyclohexylamines a “heavier” feel and is responsible for the compounds we tend to assign the feeling of “holing”. In general, compounds with 2’-Oxo substitutions seem to follow many of the same patterns seen in the non 2’-Oxo ACHs, in terms of how the amine and the length of the carbon chain on the amine affects activity.

If we want to rank the highest affinity (and likely most potent) compounds in this study, we have MXiPr>MXPr>O-PCE>Ethylmethylketamine>MXE>O-PCiPr>DCK>O-PCPr>N-Ethylnorketamine>Cyclobutylketamine>MXM>DMXE. All of these compounds are higher affinity than ketamine, and Allylketamine is close in affinity to ketamine, being only slightly less. Of these, the ones that haven’t been made yet are Ethylmethylketamine, O-PCiPr, Cyclobutylketamine, and Allylketamine. These all represent potential future developments for arylcyclohexylamines. Notably, the cyclobutyl and allyl N-substitutions conserve a good amount of activity, and are probably worth exploring as regular non-2’-Oxo phenyl substituted arylcyclohexylamines (eg, 3-MeO-PCcBu, 3,4-MD-PCcBu, 3-MeO-PCAl etc.).

 The most interesting new finding is perhaps the high affinity of the cyclobutylamine, which has not really been investigated. It would be really interesting to see what this is actually like qualitatively and how that structure affects the activity of other substituted ACH’s!

 

References:

Abelian A (2024). Design, Syntheses, and Pharmacological Evaluations of β-ketoarylcyclohexylamines. Doctoral Dissertation, Saint Joseph’s University. Astrophysics Data System.

 

Cho AK, Hiramatsu M, Schmitz DA, Vargas HM, Landaw EM (1993) A behavioral and pharmacokinetic study of the actions of phenylcyclohexyldiethylamine and its active metabolite phenylcyclohexylethylamine. The Journal of Pharmacology and Experimental Therapeutics 264(3):1401-5

 

Jose J, Gamage SA, Harvey MG, Voss LJ, Sleigh JW, Denny WA (2013) Structure-activity relationships for ketamine esters as short-acting anaesthetics. Bioorg Med Chem. 21(17):5098-106.

 

Morris H, Wallach J. From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. (2014) Drug Test Anal. 6(7-8):614-632.

 

Stevens C, Thuillier A, Taylor KG, Daniher FA, Dickerson JP, Hanson HT, Nielsen NA, Tikotkar NA, Weier RM (1966). Amino Ketone Rearrangements. VII.1 Synthesis of 2-Methylamino-2-Substituted Phenylcyclohexanones. The Journal of Organic Chemistry 31(8), 2601-7

 

Wallach J (2014). Structure Activity Relationship (SAR) Studies of Arylcycloalkylamines as N-Methyl-D-Aspartate Receptor Antagonists. Doctoral Dissertation, University of the Sciences in Philadelphia. Proquest Dissertations and Theses database.

 

Zhang Y, Ye F, Zhang T, Lv S, Zhou L, Du D, Lin H, Guo F, Luo C, Zhu S (2021). Structural basis of ketamine action on human NMDA receptors. Nature 596:301-5