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Structure-Activity Relations and Synthesis of over 70 new Diarylethylamines (Diphenidine type Dissociatives)

So many new drugs to explore!

I should note that the publication of this paper for the most part renders my old post on Diarylethylamines and the corresponding flowchart more or less obsolete. The answers I sought out in my hypothesizing in that article have largely been answered by this publication, and I am too lazy to completely revise the whole article and the chart. All the information anyone could gain from that article is more or less contained in this dissertation and even just this summmary.

Hot off the presses is the PhD dissertation of my friend and colleague Michael Dybek (you can find the full document here)- a comprehensive analysis of the 1,2-Diarylethylamines, the class of dissociative drug to which belong drugs like Diphenidine, Ephenidine, and MXP. Other compounds within this fascinating class are known to be opioids (MT-45, AD-1211, Diphenpipenol), antidepressants (Lanicemine), and stimulants (A-D2PV). This class of drugs is actually derived from the Phenethylamine structure- but there is another aromatic ring in the alpha position, and the amine is substituted to be at least a secondary or tertiary ring structure. This paper delves into an vast range of variations on that basic scaffold, analyzing how substitutions on the two rings or variations on the amine affect the activity on the NMDA receptor (In other words, dissociative activity). A total of 80 compounds, 67 of which do not yet exist in literature, are analyzed in this regard. 34 of the compounds are also analyzed for their off-target affinity at other receptors, like K-opioid, M-opioid, Sigma, and Muscarinic, and for monoamine transporters, which can modulate antidepressant or stimulant effects.

Structure of various Diarylethylamines

For the chemistry people (you can skip this bit if you’re not a chemistry person), the synthesis and analysis of every compound is extensively detailed. All of these compounds are synthesized from an incredibly simple and elegant and usually high-yielding one pot reaction- It is ridiculously accessible, save for some of the more exotic substitutions they can all be made in one step from common, inexpensive reagents- this is data that I think could revolutionize development and study of this class of compound! It is a synthesis so simple even I can do it! All are produced through a combined modified Mannich-Barbier reaction, in which the benzyl group comes from the corresponding benzyl bromide which reacts with Zinc dust. Trifluoroacetic acid helps optimize for a higher yield by etching the Zinc. This reaction was performed in THF at room temperature. After allowing the organometallic halide nucleophile to form, the amine and the α-position substitution (as an aldehyde) are added, yielding the final product which can be extracted via an acid-base workup. All of this is performed at room temperature, and most of the compounds easily crystallize (though I have to caution against using alcohols as a recrystallization solvent, as it forms a seemingly unbreakable solvate with EtOH). This simple process can offer a high yield and makes it incredibly easy to make substituted analogues. Some extra work may need to be done for certain analogues to produce certain expensive or unstable intermediates that aren’t commercially viable or to protect/deprotect to form target substitutions.

While this class of compound has a very high affinity for the NMDA receptor, with lead compound Diphenidine having an even greater affinity than even PCP, they are curiously impotent in vivo, with active doses of Diphenidine in the range of 60-140 mg in my experience. So far there hasn’t been a definitive explanation for this disparity. Also stymying their popularity is the fact that they can instill a seeming week long cross tolerance with other dissociatives- perfect for the occasional user but unfortunately not preferable for the heavy users who drive the markets. The only compounds that had a higher affinity than Diphenidine were the 2-Chloro and 2-Methyl analogue (with the 3-MeO and the 2F analogue coming pretty close too!), so it is to be expected that every other compound in this study would dose in the range of >100 mg. They are also primarily active orally, and are incredibly painful to dose intranasally. Most disso fanatics I know love snorting things, so this also takes out some of the thrill. Some experimented with vaporizing diphenidine, which apparently induced extreme compulsive redosing, with some users describing it as “dissociative crack”- though there are unconfirmed claims of toxic byproducts being produced by pyrolysis of these compounds, so I would caution against that ROA until that is studied further. Despite all these detractive qualities, I find these to be fascinating and worthwhile compounds that I encourage people to explore and hypothesize and generally be curious about! There are probably incredible, beautiful discoveries out there that have been clearly mapped out for us, just waiting to be documented!

It is a monumental work that clearly maps out development of this class of drug within the scope of dissociative activity and I encourage curious researchers to delve deep into it! It is also 604 pages long, so for people who want to know the juicy Structure Activity Relations, here is the meat of it:

First, a little nomenclature- numbered substitutions are for the α-position aromatic ring, double prime” numbers are substitutions on the benzyl ring, the amine is designated as a 6-member Piperidine (as in Diphenidine) by P, a 5 member pyrrolidine by Py, and any secondary alkyl amines by the basic alkane abbreviations (methyl, ethyl etc.). α-position denotes anything attached to the carbon that is connected to the nitrogen, the β-position denotes the next carbon over, between the α-carbon and the benzyl ring.

Generalized structure of a Diarylethylamine, showing positional nomenclature

As Diphenidine is considered the base structure and lead compound of this class, it will serve as a standard and point of reference for the other Diarylethylamines. A good number to remember is 18.2 ± 2.2 nM, this is the Ki value for Diphenidine, the number that represents its affinity for the NMDA receptor. A lower number means a higher affinity, which usually (but not always) corresponds to a higher potency.

So lets get cracking- what variations exist that are worth exploring?

First, here's the master list, with affinity for the NMDA receptor noted:

First we look at substitutions on the α-position phenyl ring. Affinity is highest at the 2 position and lowest at the 4 position. In some cases, such as a Methyl or Fluorine substitution, the loss of affinity was fairly linear, in others, such as the Chlorine or Trifluromethyl, there was a very steep loss at the 4-position to render the compound inactive.

Thus, for α-phenyl substitutions, it is clear that affinity is in rank order of 2>3>4.

There is a notable exception however- with a methoxy group, the rank order is 3>2>4, reminiscent of arylcyclohexylamines. No idea why this is the one exception. Would be curious to see if thiomethyl or ethoxy have the same trend.

Then we look at the different substitutions-

For halogens affinity rank order at the 2 position was Cl>F>Br>I. This pattern probably holds for the other positions. A CF3 substitution had an even lower affinity than Iodine.

Looking at the benzyl ring, substitutions in general had a lower affinity than substitutions at the α-phenyl ring. The rank order for substitutions at that position appears to be 3”>2”>>4”, (which also follows the SAR pattern for arylcyclohexylamines) with substitutions on the 4”-position being completely inactive. The only substitution that really appeared to yield anything in an active range on this ring was a fluorine and 3”-Me.

We can then look at the Amine- Diphenidine, with the piperidine, had the highest affinity. Pyrrolidine, and a variety of secondary alkyl substitutions were also assayed, giving us the rank order of:

P (18.2 ± 2.2) >E( Ephenidine)(66.4 ± 3.7)>iP (Isopropylphenidine)( 98.1 ± 6.3)>Pr(124.5 ± 8.9)>Allyl(161.5 ± 14.4 )>Py(280.0 ± 18.0)>cP(333.0 ± 19.8)>tB(254.2 ± 2.8)>>DPMe( 813.0 ± 7.2 ). Interestingly, the 2-Cl substitution for all of these yielded a higher affinity except for the Pr and tB amine.

Replacing the phenyl ring with a Thiophene also yielded appreciable affinity- with the 3-Thiophene being higher (48.8 ± 4.3), but with both having an affinity between Diphenidine and Ephenidine (2 thiophene was 65.1 ± 12.2). The 2-Furan saw an affinity just a bit lower than Isopropylphenidine (119.4 ± 2.1). Heterocycles, namely 2-Benzothiophene, 2,3-MD, and 3,4-MD were also assayed, with the benzothiophene being inactive, and the 2,3-MD (51.7 ± 8.4) having a higher affinity than 3,4-MD (131.2 ± 12.0, both within an appreciable range! And while these substituents had lower NMDA affinity, they displayed higher affinity for different monoamine transporters (more on that later), meaning they could see higher stimulant or even entactogenic effects relative to Diphenidine.

Disubstitutions had a lower affinity than most other substitutions.

Graphical representation of structure activity relations for NMDA affinity for ring substitutions

34 compounds were also analyzed for peripheral receptor effects. While the main focus of this post is NMDA antagonism, one of the peripheral effects I’d like to look into is at the monoamine transporters. These control the flow of the neurotransmitters Dopamine, Serotonin, and Norepinephrine. Affinity for these transporters leads to reuptake inhibition, which increases the concentration of the corresponding neurotransmitter, as seen in many pharmaceuticals like SSRI’s, NDRI’s, SDRI’s etc. Cocaine is a reuptake inhibitor for all 3 transporters! (Other stimulant drugs can modulate rote monoamine neurotransmitter flow; they are called releasers. Examples of this are NDRA’s, like amphetamine, or releasers for all 3, like MDMA. We are looking at reuptake inhibition though)

All of this is to say, the monoamine transporters are like 3 levers that can be adjusting synergistically to achieve a variety of effects.

Some patterns emerge, like DAT affinity being modulated by a rank order of 3>2”>3”>4>4”>2. So interestingly, while the 2 position strongly increased NMDA affinity, it pretty much eliminated affinity for the dopamine transporter (oddly enough with the exception of 2-Cl-DPP. Most of the compounds were not active at SERT, and those that were only had moderate affinity, with the highest being 4”-F-DPPy. All of this translates into some yet unknown complicated interworking of synergistic effects that would produce a unique subjective experience for each compound!

Graphical representation of structure activity relations for monoamine transporter affinity for ring substitutions

I know this has been a very long and dense summary (to be fair it is a vast amount of data), but I hope it can be of use to those interested enough to delve into this massive contribution to our understanding of dissociatives and dissociative structure-activity relations.

Happy explorations, fellow researchers!

2022 In Review

2022 was the single most eventful, trajectory-shifting year of my life. A lot happened. I got married to the love of my life and we live happily together. My nephew was born, the first of his generation of our family. I have had calm, reasonable discussions with my parents about drug use and our relationship is better than it has ever been. I was in the bridal party for the wedding one of my closest friends. Another one of my closest and oldest friends and recurring character in many of my reports moved several states away. I got super into Warhammer 40k, it eats up a lot of my time and energy now :p I had a sanctuary room built into my house as a wedding present and it is my paradise. I have actually finally met more of my online drug friends and fans in person which is super cool.

I lost one of my dearest friends to a drug overdose. I still have trouble grappling with their absence and will love them forever.

Perhaps most relevant and what has actually changed my life directly the most (getting married is a big deal but functionally very little changed in our lives!), I began working at a lab that specializes in the study of novel psychoactive compounds, especially psychedelics and dissociatives. To say I am honored that I get to be a part of this research is an understatement, it is the opportunity of a lifetime and I am blessed beyond measure that I had the fortune to find this position. I work entirely with chemistry, with synthesizing novel dissociatives. Chemistry is not my strong suit and it is not my background but nonetheless I persist. I have learned so much in my year in this position- it is a revolutionary workplace where drug use can be discussed openly and candidly, with dedicated passionate people on all sides who are making incredible discoveries every day. Everyone has been more than accommodating with me, a relative outsider and neophyte in the field. I am extremely excited for when we publish the projects I have been working on and I can discuss them publicly! (For now though, please do not pry me about any of our work- I will share it when I am allowed!) As much as I am passionate about drugs, about studying them and learning about their effects, about structure-activity relations and the vast taxonomy contained within- I think this has asserted that this is not what I want to do for the rest of my life, for my entire career. I am lacking so much foundation in organic chemistry and pharmacology that ultimately just makes me feel like I am treading water over an immense void every day. The work is exceptionally challenging in a way that doesn't feel manageable or sustainable for me. Perhaps this was an experiment to see if an outsider can be taught organic chemistry on the job- and I guess the answer is, I can follow directions, I can complete tasks as instructed, but I don't REALLY know what I'm doing. I don't know what is happening on a fundamental level, I cannot discuss theories or really conceive alternate solutions or explanations for when I observed things not happening as predicted (the vast majority of the time, as chemistry dictates). And it's silly to complain about, after all I have not really put in concerted effort to learn these fundamentals on the side. Perhaps at a different point in my life I would have been more than capable, but the drive and passion and motivation isn't there for me. I am mentally exhausted at the end of every day and usually just want to get home and do drugs. I have realized that ultimately, among all the passion and study, what I like most about drugs is just taking them. I am feeling my age, which is still relatively very young, but I very much do not have the time and mental energy I had when I was younger. Perhaps this is more a function of working full time and just not being able to adapt to that lifestyle- I am a born housewife admittedly. I am not sure if this is a field in which I will continue- my true passion still lies with zoology, particularly entomology or marine invertebrate zoology. I love the creatures of this world and their infinite beauty and diversity more than anything, it is one of the few things that still stirs a deep passion in me, where I feel like I could comfortably do the work indefinitely- and more importantly, it is a field where I feel like a have a definite foundation, where I am confident in my knowledge and understanding and eager to learn more, where I feel competent and well-applied. 

I am probably never going to leave the world of drugs behind, I just like them too much. This project *gestures to entire blog* will continue indefinitely, though I would expect the rate of posting to slow even more. But perhaps I will leave this world behind someday- it quickly feels like it is reaching a point of complete unsustainability. I have crossed that cursed bridge of using dissociatives just about daily, and it is very difficult to go back. Even on days when I don't use them I probably use some other drug, like benzos, misc GABAergics, gabapentinoids or opioids. I am chronically bored and understimulated, yet also chronically tired and burned out, and drugs are the only relief from both. My dissociative tolerance is creeping up. I feel I can no longer accurately report doses of things anymore, and the experiencecs with individual drugs are largely blending together into a general dissociative slush ranging from heavy-stimulating. I worry that I will not be able to report on new compounds with the detail and resolution that I was able to before. I don't like this trajectory, and I don't know any way off of it. I don't remember what it is like to live sober anymore. I get depressed and moody when I can't access my drugs of choice. I am fully, undeniably, addicted now. So long as I have access, I will use them regularly and compulsively. I do not know how I will behave if I do not have access. That situation has not presented itself yet. The only way I can forsee this concluding, unfortunately, is coming to a head and having it cause some sort of catastrophe that forces my hand in one way or another. Until then, I have established a new sickly equilibrium, a baseline comfort that is very very very hard to break. I am making a concerted effort to break out of my dissociative stasis and revisit psychedelics, especially now that I have the space to do so. 

I haven't written much this year, just a handful of reports. Lizard Labs running into legal troubles and now ending most of their dissociative production capability is a big blow to morale. Sourcing things has become increasingly difficult. I guess what I am most proud of writing is this bio-characterizing of the wholly novel dissociatives POxP and PThP.  I would love to see these explored further.

I don't think I will ever do as many new drugs as I did in 2021 and that is okay. That is not even remotely sustainable. 31 is still a lot though, this is my second biggest year in that regard. As I do every year, I am going to rank every new drug I tried in 2022. Have fun!

1.FXE - FXE is fantastic. It's not that deep. It's a lot of fun though. I can't think of a more perfect party drug. It is another attempt to hit that MXE bullseye but it also misses, because nothing will be MXE. But it works well on its own. Its forgiving, stimulating, casual and fun, I could do this forever. It's so great. It can be profound if you really force it to be. It is not as profound as DMXE. But it doesn't need to be that, sometimes you just wanna have fun with your friends.

2. 1,4-BDO - GHB, 1,4-BDO, GBL, its all the same. This is a lovely compound for casual use, just quite dangerous in its interactions. I would describe it as Alcohol combined with MDMA without the negative qualities of either (the overstimulation, the nausea and headaches). Aphrodisiac, nostalgic, heavy and comfortable.

3. 1D-LSD - The 1-substituted LSD analogues are interchangeable but this is by far the most potent one that has been made. I love LSD. So I love this. Very simple.

4. Bromazepam - The benzodiazepine that is probably the most reminiscent of etizolam. Euphoric, not too sedating, medium duration, what's not to love.

5. Fluclotizolam - A benzo that is both useful and fun! Great to get to sleep quickly with no hangover. Pleasant and euphoric for just hanging out otherwise. Very agreeable.

6. Isopropylphenidine - Bright, visual, functional diarylethylamine. Notable for how easily I could slip between a heavy dissociative experience and full functionality.

7. Hydromorphone - Short warm simple opioid. Yum. 

8. TMA-2 - Intense and bright and colorful and so so so euphoric but god damn is it all tempered by a vicious body load. 

9. DOC - An incredibly vast and challenging psychedelic. Heavy body load. Intense in a way I haven't experienced in a while. This is beyond the realm of rankings of favorites, just a hefty drug in general, fascinating but so mighty.

10. Deschloroetizolam - Medium length benzodiazepine, but very neutral in terms of euphoria or sedation or anything. Grey, middle of the road, but not bad in any way, still nice.

11. Lemborexant - Makes me sleep. Nothing else. Useful. Can have grogginess the next day though.

12. 4-MetMP - More or less reminded me of 4F-MPH. Same issues with side effects at higher doses. 

13. HHC - Sleepy alt cannabinoid, nothing too exciting

14. Tapentadol- It is an opioid that makes me hear voices. Nice enough I guess. Kinda unnerving.

15. 2B-DCK- What if you just took ketamine and made it less potent  and also shorter lasting. This is one for enthusiasts of snorting enormous quantities of powder. If you're not into that there isn't much value here. Not really any unique qualities. Bulkier halogens are diminishing returns.

16. Propylhexedrine- Bitter benzedrex, I don't like stimulants, I don't like this one. Mostly uncomfortable.

17. Nalbuphine- Definitely an opioid but it just made me feel bad. Straight up dysphoric. Sad as hell.

18. Zopiclone- Feels kinda like zolpidem but not as fun. I got *that* side effect, where everything tastes like bitter metal for the next 24 hrs. Not worth it.

19. PCM- I snorted it and it just hurt and tasted bad and nothing happened. On paper it's psychoactive though. I'll let someone else figure it out.

Needs further exploration:

P2AP - Adamantane analogue of PCP (Adamantane instead of the cyclohexane), I have been titrating this up very slowly and steadily but honestly it scares me. The duration could be immense. It might be a powerful anticholinergic etc. I feel bad, I was not a very good test subject for this, I keep procrastinating on working the dose up.

Desalkylgidazepam - I just wasn't able to find consistent information on this one so I didn't know where to start. I don't have the time or motivation to dose titrate benzos.

Emylcamate - No one likes this one. I am working on finding out why. Not eager to do that though.

2-TFM-Diphenidne - Maybe threshold effects at 120 mg. Maybe not. Need to explore further.

O-PCiPr - It's a dissociative, that is all I can say for now.

Tofisopam - Supposedly the anxiolytic effects of benzos without the sedative or amnesic effects. I haven't given the time to exploring it.

Promethazine - Combined it with codeine pills for uhh I guess you would call it solid lean. Haven't taken it by itself.

3'-MXP - I am not confident this is active. That 3' denotes that the methoxy group is on the benzyl ring, not the alpha phenyl ring like MXP. 

PCPy - Was sent a small sample of this. I am not sure why I haven't explored it earnestly, I think I forgot, this is a good reminder! I tried it once, it felt similar to 3-Me-PCP but I didn't catch a lot of the details.

Banisteria caapi  - I smoke it. It has an interesting light stimulating effect and something else that's hard to place. But I haven't dived too deep.

Muscimol - A. muscaria extract that was decarboxylated to yield primarily muscimol. We truly live in the future! I have found it to mostly just be sedating, in the way that benadryl is sedating. Need to explore higher doses.

NEP- Honestly I only took it while I was already on benzodiazepines. I am not sure. I think it was fun though.