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
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