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Efavirenz: New starting point for 5-HT2a agonists

SeenSoFar

SeenSoFar

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Jun 21, 2013
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300px-Efavirenz_skeletal.svg.png

So, it's long been known, or at least rumoured, that efavirenz, an anti-retroviral drug used to treat HIV infections, is abused in South Africa for it's supposedly hallucinogenic effects. The cause of these effects has been speculated upon, but until today I had never heard of any actual research on the subject. However, today I read a paper[1] that said efavirenz has been shown to be active at the 5-HT2A receptor, among other targets of interest, and that it induces the characteristic head-twitch response that identifies psychedelic effects in rodents, as well as substituting for LSD in lever-pull discrimination tests in trained rodents.

It seems to me that efavirenz should be used as a starting point for the development of new psychedelic compounds, since anything that came out of it would be totally dissimilar to current controlled compounds. The real question would be whether the anti-retroviral activity, and the host of negative effects that can occur with the use of efavirenz could be separated from the psychedelic effects.

Thoughts?

[1] - Neuropsychopharmacology (24 May 2013) | The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties - http://dx.doi.org/10.1038/npp.2013.135
 
It actually has a pretty similar backbone to RH-34 which is the psychedelic based off the 5-ht2a antagonist ketanserin.
 
chaos_destroy said:
It actually has a pretty similar backbone to RH-34 which is the psychedelic based off the 5-ht2a antagonist ketanserin.
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I've not failed to notice that one either, believe me. I actually have a tonne of RH-34, but I've not assayed it up to anything beyond threshold levels, which were achieved in the low-milligram range. For some reason I've been fascinated by RH-34 from the moment I heard about it, I think because it is so different from any other psychedelic that is known, so it's a lot father into unknown territory than say, an untested phenethylamine 4-substitution is. I still am holding out hope that one day I will find an active level for RH-34.

Anyway, to get back on topic, the comparison to lorcaserin is an interesting one. Although they seem significantly different at first glance, similarities do begin to emerge after some closer examination. The thing that is striking to me, however, is that the SAR for this as a 5-HT2A agonist would be something totally new.

Now, that being said, one could argue that there are similarities between the ring system of efavirenz and an indole ring. If you look at efavirenz flipped vertically from the perspective shown in the skeletal formula at the top of this thread, you can sort of squint your eyes and make the case that this is a heavily substituted six membered indoleamine analogue. The obvious difference among obvious differences is that where the ethylamine side chain would be on an indoleamine, there is instead a trifluoromethyl and a cyclopropylethynyl group. VERY interesting SAR going on here...
 
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If you look at the RH-34 paper below it shows how they think it docks in the 5-HT2a receptor along with the tryptamine and PEA N-benzyl analogues. The ketone (equivilent to the one still in Efavirenz) and the amine/amide group appears to interact with the same residues that the indole amine and PEA 2-methoxy groups do.

The interesting thing is that Efavirenz doesn't have a ethylamine side chain which is present in RH-34, tryptamines and PEAs. Though if you look at how RH-34 docks it looks like the side chain of Efavirenz would go to the same pocket that the N-(2-methoxy)benzyl group does around V366 and I152. That would put the chlorine group at the same position the the 5-meo groups sit in the tryps and PEAs. Would be interesting to replace it with a methoxy group. Or move it one position over to the equivalent 4- postion as PEA's along with the methoxy.

Also obviously replacing the Efavirenz side chain with a ethylamine or ethyl(n,n-dimethylamine) side chain would be interesting though then you are kind of going too far backwards perhaps. Although it would still be one position over.


Silva, M. E., Heim, R., Strasser, A., Elz, S. and Dove, S. (2010). "Theoretical studies on the interaction of partial agonists with the 5-HT(2A) receptor." J Comput Aided Mol Des.
 
chaos_destroy said:
If you look at the RH-34 paper below it shows how they think it docks in the 5-HT2a receptor along with the tryptamine and PEA N-benzyl analogues. The ketone (equivilent to the one still in Efavirenz) and the amine/amide group appears to interact with the same residues that the indole amine and PEA 2-methoxy groups do.

The interesting thing is that Efavirenz doesn't have a ethylamine side chain which is present in RH-34, tryptamines and PEAs. Though if you look at how RH-34 docks it looks like the side chain of Efavirenz would go to the same pocket that the N-(2-methoxy)benzyl group does around V366 and I152. That would put the chlorine group at the same position the the 5-meo groups sit in the tryps and PEAs. Would be interesting to replace it with a methoxy group. Or move it one position over to the equivalent 4- postion as PEA's along with the methoxy.

Also obviously replacing the Efavirenz side chain with a ethylamine or ethyl(n,n-dimethylamine) side chain would be interesting though then you are kind of going too far backwards perhaps. Although it would still be one position over.


Silva, M. E., Heim, R., Strasser, A., Elz, S. and Dove, S. (2010). "Theoretical studies on the interaction of partial agonists with the 5-HT(2A) receptor." J Comput Aided Mol Des.
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That's very interesting information that you have provided, thanks so very much!

I actually like your idea of replacing the cyclopropylethynyl and trifluoromethyl sidechains with something more conventional. One of the goals that would have to be met before homologues of efavirenz could ever hope to be viable psychedelic compounds would be the elimination of anti-retroviral activity and any sort of organ-damaging effects, which have been reported with efavirenz, and replacing the bizarre and esoteric sidechains with something a little more conventional in the world of psychedelic compounds seems as good a place as any to start.

I think that we need to start moving away from the tryptamine and phenethylamine backbones and trying to find novel pharmacophores with activity as psychedelics. Who knows, one could turn out to have the magic of LSD. The point is, these compounds show us that there's no need to limit ourselves to tryptamines and phenethylamines, and that a whole wild world of undiscovered psychedelic treats lies just beyond the horizon.

Again, thank you so much for sharing that excellent paper with us. It provides really awesome info!
 
SeenSoFar

You seem glowingly optimistic. Here is a juxtaposing anecdote. I obtained 25B-NBOMe after learning the chemical was extensively tested at higher than recreational doses in rats, pigs, and primates without obvious ill effects. This chemical was involved in human clinical trials. This chemical has been responsible for multiple fatalities and nearly killed me at normal doses.

With large amounts of money multiple people with PHDs miscalculated the potential harm of this drug. These people had millions of dollars of equipment at their disposal and decades of combined experience in drug design. If they can't make unique safe and selective 5ht2a agonist what makes you think you could?
 
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You mentioned something like that to me....
what happened to you and have you reported on it elaborately in PD?
 
Panic attacks aren't life threatening, though? To say it nearly killed you because you had a bad experience and felt funny the day after (and never confirmed anything with a doctor) seems like a bit of a stretch.

If you experience someone going out of control, or having a seizure, or otherwise acting very strangely after having taken NBOMes, you should get in touch with emergency medical services. There's little you can do on your own to support someone having an overdose other than wait by their side.

with regards to NBOMes: Some deaths are from self-injury. Some deaths are from seizure and/or aspiration and could be prevented by putting the person in the recovery position. The serotonin 5ht2a receptor is also present on platelets and can cause them to form clots, so some deaths could also be from that. What is certain is that many deaths occur at doses higher than 1mg or in cases where the people don't even know the dose.

These drugs are incredibly potent serotonin agonists with a steep dose response curve. Part of the problem is that many people immediately jump into ridiculously sized doses, or they redose during the experience, or they get ballsy and figure "if one milligram is fine then two is better". 200 micrograms can be the difference between a tolerable trip and an overwhelming one. You have to excercise the utmost caution with these substances.

These drugs are an order of magnitude easier to make than LSD, and thanks to the joy of the information age, it's almost too easy to learn about them. It seems natural enough to me that lots of people would be using them (LSD in the 60s anyone) and as a result you would also see a lot of documented negative reactions, fatalities, etc.
 
FunctionalOlfactio said:
SeenSoFar

You seem glowingly optimistic. Here is a juxtaposing anecdote. I obtained 25B-NBOMe after learning the chemical was extensively tested at higher than recreational doses in rats, pigs, and primates without obvious ill effects. This chemical was involved in human clinical trials. This chemical has been responsible for multiple fatalities and nearly killed me at normal doses.

With large amounts of money multiple people with PHDs miscalculated the potential harm of this drug. These people had millions of dollars of equipment at their disposal and decades of combined experience in drug design. If they can't make unique safe and selective 5ht2a agonist what makes you think you could?
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You seem to have missed my point. I've never said I was going to make anything. My o-chem knowledge and experience is currently far too incomplete to synthesise something myself, but that's besides the point. Even if developing a synthesis for a novel compound and carrying it out was within my current capabilities, I wouldn't be doing it. It doesn't take a genius to see that such a course of action would be asking for trouble.

My point was this: seeing that efavirenz has been shown anecdotally to be an enjoyable psychedelic, and that these effects have been shown to come from agonism at an interesting target, it would be logical for someone with the right resources and expertise to explore analogues of this compound. For me, it's exciting to see a new pharmacophore that could potentially lead to a while new series of compounds with interesting effects, that doesn't mean I think we should dive in face-first and just "make 'em and taste 'em". Don't mistake my enthusiasm for foolishness. I'm no ShaggyFin...
 
I've been thinking about this for a while now and came up with an analogue in between this and Ketanserin, anyone know if or not it would work?

KaOG950.jpg


It was just playing around, the bottom piperidine ring would be to increase potency (but it could be a straight benzene ring also) as Efavirenz itself isn't all that potent but would the Ethynyl/CPM group be essential for serotonergic activity or not? In fact, what are the essential parts of it for it to be both seretonergic & GABA-ergic?
 
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blueberries said:
I've been thinking about this for a while now and came up with an analogue in between this and Ketanserin, anyone know if or not it would work?

KaOG950.jpg


It was just playing around, the bottom piperidine ring would be to increase potency (but it could be a straight benzene ring also) as Efavirenz itself isn't all that potent but would the Ethynyl/CPM group be essential for serotonergic activity or not? In fact, what are the essential parts of it for it to be both seretonergic & GABA-ergic?
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too many bonds on that nitrogen up there.
 
Yeah, must have passed my mind as I was doing it. I was more concerned with the bottom groups. Just consider it a single methyl instead.
 
blueberries said:
Yeah, must have passed my mind as I was doing it. I was more concerned with the bottom groups. Just consider it a single methyl instead.
Click to expand...
A single methyl on the nitrogen? or the nitrogen is now a carbon? In any case I think you need the nitrogen to be in the same state as already tested psychedelic phenthylamines. Notice the the similarities: halogen on the 4 position on the phenyl. an amide stemming from that. What we really have to do is figure out what makes it so we can put the amide next to the phenyl, and not after an ethyl.
 
I came up with some simpler versions that I think could be a good starting point. It's mixed with bk-2C-B. Would these be any good?

demq9s.jpg
 
DL-ark said:
A single methyl on the nitrogen? or the nitrogen is now a carbon? In any case I think you need the nitrogen to be in the same state as already tested psychedelic phenthylamines. Notice the the similarities: halogen on the 4 position on the phenyl. an amide stemming from that. What we really have to do is figure out what makes it so we can put the amide next to the phenyl, and not after an ethyl.
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I was meaning a single methyl on the amine but going by what phenethylamines look like, the amine shouldn't really have anything on or it should be either a methylamine or etthylamine group at that position. Then again it wouldn't really look like an efavirenz/ketanserin analogue, so it's a tricky choice to make. Perhaps also making that hydroxy on 3 a methoxy ala PEA's.
 
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