Generalized structure of a Dioxolane compound with NMDAr antagonist activity |
Coming back to add a third addition to
my series on the structure activity relationships of various compounds, I first
touched on Arylcyclohexylamines and Diarylethylamines.
Dioxolanes dioxolanes how I would love
to meet a dioxolane on the street some day! I have written a good bit on thesecompounds in the past. A good generalized but detailed introduction to this class of chemicals can be found in that article! These are curious characters that I personally
believe hold a lot of potential. An untapped mineral vein, gleaming in the
dark-
Overall, dioxolanes are fairly
unpredictable when modified and there seem to be a range of cryptic patterns or
lack thereof with their SAR, rife with exceptions and anomalies. It is for now,
very hard (for me at least) to conjecture what may or may not be active.
Dioxolanes never had the distinction
of making it to the recreational market. I have no knowledge of what the
clandestine chemistry scene around dissociatives was like in the early 2010s
but it seems like the only jump to a different class of molecules was driven by
a UK ban on aryclyohexylamines. At that point there was a buffet of available
options for the enterprising novel psychoactive chemical developer- The
diarylethylamines ultimately took the prize, but the dioxolanes must have been
considered then. Why did they remain relegated to the dustbin of history?
Only two were ever tested on humans
and most literature on developing other Dioxolanes uses them as standards.
These are Etoxadrol and Dexoxadrol.
When one delves into the medical
literature on dioxolanes they encounter a lot of interesting comments on
dioxolanes-These are excerpts pulled from my article on them, the citations can
be found there!
“Open eyed hallucinations were not observed in
post recovery, though subjects observed a "dream state" while
anesthetized
"None of these dreams carried connotations
of unhappiness to the individual; in fact, the majority were described as
pleasant and/or unusual experiences. Consistent ideas of depersonalization,
primarily of malinterpretations of self anatomical configurations, were a
prominent symptom”
"The
side effects caused due to the medication of Dexoxadrol are quite unusual and
dangerous. It causes hallucinations and nightmares in the users. It has been
reported that Dexoxadrol creates unpleasant conditions before the users. The
dreams that came after the usage of this medicine range from pleasant to
frightening. In dreams, it seems as they are in some other world that has no
relation to the reality. But in most users, the results are outstanding rather
than insane."
In most
literature these effects can seem alarming, dysphoric, perhaps not particularly
appealing. Perhaps it was this that turned research chemical designers off from
developing them any further. Sensations described as vivid “dreams” or
“nightmares” along with open eyed hallucinations were frequent. I hypothesize
however, that what were referred to as dreams or nightmares were actually akin
to dissociative “holes”- semiconscious states heavily laden with visuals, even
visuals that bore a narrative- if this is the case then these would certainly
be very interesting substances! It believe that at the time the medical
literature simply lacked the vocabulary to do define those states as such.
Other effects of the dioxolane experience were defined as “PCP-like”, while
other side effects noted as concerning seemed to be exact descriptions of the
qualities of a typical dissociative experience.
Nonetheless, this research was shortly after PCP had become an unexpected problem child in the world of anesthetic development. Seeing similar effects, it was possible that researchers quickly aborted trials and swept this class of chemicals under the rug to avoid repeating the trials and tribulations that came about through the lifespan of PCP. Meanwhile, the questionable, though I argue dated, descriptions of the experience from the contemporary literature may have turned future research chemical developers off from exploring this class of compounds further. Not only may they be very intriguing, but so far most have shown to be sufficiently potent, with dosages from 10-50 mg across the family depending on the compound and ROA. I personally believe that it is worthwhile to give this class of chemicals another shot!
So how
do you go about designing novel chemicals in this class?
First,
I must share the disclaimer I always share when dispensing this kid of
information-
The
safety profiles of the dioxolanes is entirely unknown. The only reference we
have for doses is via IV, active doses by common oral, rectal, and intranasal means
are entirely unknown. They have only seen limited human trials with only 2
compounds, which leaves a lot of unknowns. It is known that an accidental
overdose of over 6x the intended dose was not fatal, though it yielded a long
and difficult experience [7]. It appears that it is well tolerated for acute
toxicity with minimal dangerous side effects. The effects of chronic use and
chronic toxicity of dioxolanes is entirely unknown and this should be
approached with the utmost caution. The risk of accidentally producing toxic
byproducts from improper synthesis is also entirely unknown to me.
A
warning about dissociatives in general, sources cited in this article:
“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.”
Here’s
a handy flowchart to assist you!
For an enlarged version of this image: https://i.imgur.com/3v6qKnx.png
For a download of a pdf of this chart: https://gofile.io/d/h05j2m
What
are the exact details of the SAR of this class of compounds and why did I include
what I did? Let’s get into it.
Working
our way down from the top of the molecule-
Starting
with the amine: In the dioxolanes that have seen in vivo usage, this is a
2-piperidine. One attempt was made however, to replace this with a simple primary
amine on an ethylamine chain extending from the dioxolane. In this case, a trans
analogue of etoxadrol with an ethylamine was one of the only compounds to show
any activity, and it was much less than that of base etoxadrol [1]. Even more
promising was the 2S, 4R enantiomer of this same compound, which saw increased
potency, though not quite as much as etoxadrol [1]. This has broader
implications for potentially attempting other amines beyond the standard
2-piperidine. It appears there needs to be at least 2 carbons between the
dioxolane ring and the nitrogen to conserve activity- necessitating an
ethylamine. While the primary ethylamine has been demonstrated to be active in
vitro, a secondary ethylamine (as seen in the standard piperidine ring) may
also be active, yielding an immense variety of potentially active variations.
Beyond that, a tertiary amine appears inactive [6]. A Pyrollidine instead of a piperidine has
also been attempted but was found to be inactive [6]. So it all seems quite
fickle and hard to predict.
Working
with a piperidine however, many other little tidbits are known. For one, the
nitrogen must remain as a secondary amine- as mentioned above, adding
substitutions to turn it into a tertiary amine greatly decreases activity [6].
Secondly, NMDAr antagonist effects are conserved (and potency either retained
or increased!) with very specific substitutions on the 4 position of the
piperidine ring. It seems to be fickle for which substitutions it’ll accept
however. So far it has been demonstrated that a Dexoxadrol substituted with a
4-Fluorine on the piperidine is even more potent in vitro than Dexoxadrol alone
[3]. A Difluoro substitution also appeared sufficiently active [3]. A Hydroxy
group is also tolerated [2]. The 4-fluoro and 4-Hydroxy analogues of Dexoxadrol
have been named WMS-2539 and WMS-2508 respectively. Meanwhile, a double bonded
oxygen, forming a 4-piperidone, is hardly active, as is a 4-methoxy group, as
is any kind of 4-amino group [5] [2]. This makes it hard to guess what can and
cannot be placed there (for me at least). Perhaps other halogens would work,
either in mono- or di- form. Perhaps a methyl group though it seems unlikely
that anything extending beyond that would remain active, ass activity on those
substitutions is hypothesized to be correlated with bulk be (by my conjecture)
that a substitution larger than ~30 u will not be tolerated (though multiple
substitutions can still be affixed to the same spot, even if they cumulatively
have a mass greater than 30 u!). The amino substitution has less bulk than
that- but perhaps there is something in the unique properties of the nitrogen
that precludes activity. As for substitutions on other parts of the piperidine ring?
They haven’t been attempted and so far no one knows how they might behave.
Next we
move on to the next component- the eponymous Dioxolane ring. Several studies
attempted to expand the dioxolane ring to a 6-member Dioxane ring. It was
apparent that this greatly decreased activity in most circumstances [1] [6] [5].
The Dioxolane ring is important.
There
is of course always an exception- if the piperidine ring is replaced with an
ethylamine with a primary amine at the end, then NMDAr antagonist activity is
yet again retained. This suggests an entirely new class of compound closely
related to the dioxolanes called the dioxanes- a 6 member 2-oxygen ring (as a
1,3-dioxane) with an ethylamine chain instead of a piperidine [5].
Structure of a hypothetical 1,3-dioxane based compound with a primary amine |
So now
we move onto the next options at our disposal- an aromatic ring and some other
functional group bonded to the same quaternary carbon on the dioxolane ring.
Etoxadrol sees that functional group as an ethyl, while dexoxadrol sees a
second phenyl ring. In all drugs that have been attempted in vivo, the aromatic
rings were phenyl rings. However, one example that showed NMDAr antagonist
activity in vitro and equivalent or slightly less potency to etoxadrol was an
analogue of etoxadrol with the phenyl ring replaced with a thiophene, just as the
thiophene would differentiate TCP from PCP. The 2-Thiophene showed less potency
than the 3-Thiophene [6]. So in any variation of a dioxolane, it is feasible to
replace the lower phenyl ring with at the very least a thiophene, if not other
aromatic rings. As activity can be conserved with two aromatic rings bonded to
the same spot, different aromatic rings could even be mixed and matched if it
was synthetically feasible. The bottom line however is that there must be at
least one aromatic ring. As for the other spot on that carbon?
The
golden standard has been a simple ethyl group. One study demonstrated in vitro
that other alkane chains, from a propyl to a butyl, also conserved an
appreciable amount of activity [5]. The most potent compounds had the phenyl
ring matched with either a propyl or isopropyl group [5]. It is unknown what
else may be possible: Halogenated groups, ethers and thioalkanes, esters, other
aromatic rings, various heterocycles- there’s nothing that indicates to me that
these wouldn’t be possible!
The
last option for modification is adding substitutions to the aromatic ring (in
this case, and rather by default, a phenyl ring). 2-Cl, 3-Cl, 2-F, 3-F, 3-OH,
2-OH substitutions retained an appreciable level of activity [5] [6]. Activity
doesn’t seem consistent across position no matter the class of substitution-the
hydroxy substitution (already fairly impotent), sees an even further drop in
activity on the 3-position, as does a Fluorine substitution (though they still
show an appreciable level of activity, the drop in potency is still remarkable!)
[5] [6]. Substitutions on the 4 position were consistently inactive [5]. This
suggests that the main suite of substitutions seen on dissociatives will
conserve activity if on the 2 and/or 3 position variably, one way or another.
Perhaps the usual alkanes, and alkoxy groups could also retain activity there. The most off-the-wall substitution that saw retained activity was working a diphenylazepine (that is 2 phenyl groups on an aromatic 7 member ring) onto the R1 and R2 positions [6].
As far
as stereochemistry is concerned, it appears that only the (+)-enantiomer of any
enantiomeric compound is active as an NMDA antagonist. Racemic mixtures will
see the potency cut in half and the (-)-enantiomer has so far been demonstrated
as inactive [4].
As for nomenclature? No logical patterns
have been established- the 2 named compounds (Etoxadrol and Dexoxadrol). have
an informal naming structure, with one of them, Dexoxadrol indicating that it
is merely the dextro-isomer of the parent compound, Dioxoadrol. The names give
little indication of structure, beyond the mention of an ethyl group in Etoxadrol.
Thus for compounds developed further, a new nomenclatural scheme will have to
be developed.
The name can be prefixed with the
relevant substitutions that have been added to the molecule. The suffix
-oxadrol, can be kept, and if a piperidine as the amine is assumed to be the “default”,
then modifications of the amine can be worked into this name. So if there’s an
N-propyl tertiary amine, for example, the compound would bare the suffix of “N-propyloxadrol”.
The two moieties on R1 and R2 can then be worked into the name. The name of the
R1 aromatic ring should always come second. Thus, Etoxadrol would in this schematic
be renamed to Etphenyloxadrol. Dexoxadrol would be Diphenyloxadrol. If for example,
a methoxy group or a chlorine was paired with say, a thiophene, the names would
respectively be Methoxythiophenyloxadrol or Chorothiophenyloxadrol. If you were
to pair these with, for the sake of example, a sec-butyl secondary
amine, they would yield the unwieldly names Methoxythiophenyl-N-sec-butyloxadrol
or Chlorothiophenyl-N-sec-butyloxadrol respectively. If an oxane ring is used instead of a dioxalane,
the suffix can be modified from -oxadrol to -oxanadrol.
Sources and Further Reading:
[1]- Aepkers M, Wünsch B (2005)
Structure-affinity relationship studies of non-competitive NMDA receptor
antagonists derived from dexoxadrol and etoxadrol. Bioorg Med Chem.
13(24):6836-49.
[2]-Banerjee A, Fröhlich R, Schepmanna
D, Wünsch B (2010) Synthesis and NMDA receptor affinity of dexoxadrol analogues
with modifications in position 4 of the piperidine ring. Med. Chem. Commun.
1:87-102
[3]-Banerjee A, Schepmann D, Köhler J,
Würthwein E-U, Wünsch B, (2010) Synthesis and SAR studies of chiral non-racemic
dexoxadrol analogues as uncompetitive NMDA receptor antagonists. Bioorganic
& Medicinal Chemistry 18(22):7855-7867
[4]- Jacobson AE, Harrison EA, Mattson
MV, Rafferty MF, Rice KC, Woods JH, Winger G, Solomon RE, Lessor RA, Silverton
JV (1987) Enantiomeric and diastereomeric dioxadrols: behavioral, biochemical
and chemical determination of the configuration necessary for
phencyclidine-like properties. Journal of Pharmacology and Experimental
Therapeutics 243(1):110-117
[5]- Sax M, Fröhlich R. Schepmann D,
Wünsch B (2008) Synthesis and NMDA Receptor Affinity of Ring and Side Chain
Homologues of Dexoxadrol. European Journal of Organic Chemistry:
6015-6028
[6]- Thurkauf A, Mattson MV,
Richardson S, Mirsadeghi S, Ornstein PL, Harrison EA Jr, Rice KC, Jacobson AE,
Monn JA (1992) Analogues of the dioxolanes dexoxadrol and etoxadrol as
potential phencyclidine-like agents. Synthesis and structure-activity
relationships. J Med Chem. 35(8):1323-9
[7] -Wilson RD, Traber DL, Barratt E,
Creson DL, Schmitt RC, Allen CR (1970) Evaluation of CL-1848C: a new
dissociative anesthetic in normal human volunteers. Anesth Analg.
49(2):236‐241.
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