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Acid, dragonflies and the 5HT2A receptor

fastandbulbous said:
why does an alpha-methyl group sticking out seem to increase potency

Because it inhibits metabolism to the inactive compounds (it's why 2,4,5-trimwthoxyamphetamine is active, but 2,4,5-trimethoxyphenethylamine isn't). Means that more of the drug actually makes it to the brain. It appears that the alpha methyl group is acceptable, but increasing it to an ethyl group really hinders receptor binding
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I don't think that inhibition of metabolism is all, because then 2C-D would attain the potency of DOM if taken while on MAOIs. This is not the case. 2C-D acts somewhat longer if MAO A & B are inhibited (by moclobemide and selegeline), but potency is not increased.
 
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Because of the formation of optical isomers, one of the optical isomers has the same absolute configuration of the LSD molecule at that point and has a higher binding affinity than the other (which is 'the wrong way around' my analogy is a left handed guitar player being given a right handed guitar to play) must play some part, but the higher resistance to metabolism by MAOI will also be important. As mentioned on the original post, this is most noticable in the compounds with a ring substitution pattern most like MAO's usual substrates -anything with an oxygen on ring position 3 and/or 4 (TMA-2/2,4,5-TMPEA; MDA/3,4-MDPEA and MMDA/3-M-4,5-MDPEA aka lophorine).

The alpha methyl group also alters the octanol-water partition coefficient (giving an index of how quickly it crosses the BBB). Not sure if this last bit is a typo, but 2C-B isn't like DOM, so comparisons are vague at best. Given enough though, 2C-B is capable of producing DOB like symptoms, and moclobemide is a competetive inhibitor - it's not an absolute inhibition (the harmala alkaloids are competetive MAO-A inhibitors)
 
Well I'd say that if you used non-competetive inhibitors (like phenelzine), you'd be able to get the potency of 2C-D to approach somewhere in the region of DOM's dose, the difference being due to the factors I'd mentioned in my previous post. Of course, due to the possible pressor nature of 2,5-dimethoxyphenethylamines, your blood pressure might be through the roof, or so low as to have you pass out. Amphetamines survive because they are bad substrates for MAO, only a small part is due to inhibiting it's activity w.r.t. other amine neurotransmitters
 
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No that their appears to be some anecdotal evidence that bromo-dragonfly is not as active (at least orally) as suspected, what implications does this have for fnbs theory?

It certainly re-inforces bilz0r's earlier point that receptor affinity increases don't necessarily lead to potency increases.
 
^^

Well i'm currently high on some bromo-dragonfly, about 600ug, i'll post a trip report - but yeah at least orally its nowhere near LSD's potency, but i heard possibly if taken by other routes other than orally it might be a lot more potent.

... still right now i'd much rather be on a couple hits of acid ;)
 
Doesn't really effect the basis of what I was saying, as the compound is of the expected activity when administered IM. The problem appears to be that it is broken down in the gut, so it never gets the chance to enter the brain. When the gut is bypassed, it still behaves as expected
 
I also happened to stumble across a rather interesting paper * that details some very potent amphetamine derived 5HT2a agonists.

Although N-substitution of the DOx series usually almost abolishes psychedelic activity, the compound shown below has a binding affinity very close to that of LSD

59655N-substituted_DOI.JPG


As you can see, the N-substitution will perfectly overlay the structure of LSD, allowing for greater binding. In theory, this should happen with all of the DOx series which is N-substituted with the the N,N-diethylpropionamide group



* - Quasi-atomistic Receptor Surrogates for the 5HT2a Receptor: A 3D-QSAR Study on Hallucinogenic Substances
 
^Just a few days ago I downloaded all the Rhodium files from the Erowid archive and I remember seeing this structure when going throught the papers. However, as far as I remember were these not experimentally measured values, but rather numbers they calculated using the 3D-QSAR model they have developed. In this case they ain't worth a fart...

The relevant receptors can be quite fussy which can't be captured appropriately with a QSAR model. For example, 6-nor-LSD is inactive, so the above molecule should be inactive as well, because it's a secondary amine and not a tertiary like in LSD.
 
Oops - yes it's theoretical figures.

That said, you can't rule it out as the psychedelic phenethylamines are primary amines so they don't strictly fit the LSD model either (I'm still a bit puzzled over that)
 
I didn't mean to rule out that the above molecule will be active. What I meant to say is: there's only one way to find out if it is active as predicted: make it and test it. Since 3-chloropropionyl chloride is commercially available it would be an easy task to make this compound.

Another idea not related to this structure is to use the same rigid pyrrolidinylmethyl sidechain in PEAs which has proven to bring maximum potency to tryptamines:
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The 4-OH-indole derivative is the most potent 'tryptamine', in rat drug discrimination equipotent with DOI and about 1/10 of LSD. It would be interesting to know how the activity of PEAs responds to this modification.
 

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^ Have you noticed that the most active isomers have the different chiral configuration to all the other optically active phenethylamines and tryptamines. For all the optically active 5HT2a agonists, the most active isomer shares the same absolute configuration as LSD about the carbon at the 5 position, except for these pyrrolidinylmethylindoles.

I'm stumped as to an explanation for it
 
Has anybody come across any other active 5HT2a agonists that go against the grain in terms of the stereochmistry w.r.t. LDS/ergolines?
 
BilZ0r said:
How come ergine/LSA isn't potent?
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The exposed nitrogen reduces the rate of passage through the blood-brain barrier while increasing its metabolism to inactive product. This has the effect of increasing the duration of the experience while diminishing its intensity.
 
Great discussion. BTW, how about a 4-bromo-N,N-diethylpropionamide-dragonfly?
 
Hmm, I searched the literature and the net and I can't find anything on that. Obviously, if the theory presented here is correct, then LSA should have about the same affinity as LSD (which, btw, isn't all that high) for the 2A receptor. If it turns out not to, then we have to reexamine fastandbulbous's case.
 
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