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!
