N,N-Diethyl-3-{[1-(4-iodo-2,5-dimethoxyphenyl)propan-2-yl]amino)propanamide

[Deinonychus]

Hi guys! So a thread popped up in PD about how this fellow got something that was active at the level of 100 micrograms but which was supposedly neither LSD nor AL-LAD. He wanted help identifying it, which will be futile for the obvious reasons, but it brought something to mind. I noticed this compound in a paper a month or two ago and I've been meaning to post about it here in ADD since then, but kept putting it off. So I'm doing that belated posting now.

The compound in question is N,N-Diethyl-3-{[1-(4-iodo-2,5-dimethoxyphenyl)propan-2-yl]amino)propanamide. This substance had the highest binding affinity at 5-HT2a of any agonist or partial agonist in the paper I read, though they left LSD and the N-benzyl PEAs out. Still, it looks like it's got a rather high binding affinity, and has a curious structure, so I wonder what you all think of it from the perspective of SAR. Yeah, high affinity at 5-HT2a isn't the sole criterion for a possibly cool psychedelic (ie a high affinity for a different subtype may lead to the Phenfen cardiovascular problems, or anxiety, or whatever, possibly negating any value as a paychedelic derived from its action on the 2a subtype) but it certainly is pretty much required. I don't know much about SAR beyond the obvious stuff, like 4-position substituents on vanilla PEAs or alkyl substituents on the aliphatic amine of a tryptamine, so I figured I'd bring the compound to your attention if it hasn't already become known to you.

It looks like this:

Ki of 3.2 nM, compared to 2.5 nM for LSD, which wasn't one of the substances studied in the paper (this compound I'm posting about had the greatest affinity of the compounds they did include in the study).

The paper is: 'Quasi-atomistic Surrogates for the 5-HT2a Receptor: a 3D-QSAR Study onHallucinogenic Substances', it's available on bitnest. I'm pretty sure all the days was derived in silico. Curiously the iodine substituted form beat out the chlorinated and brominated versions, at least in the computer. The researchers describe it as a hybrid structure between PEAs and LSD, I definitely see where they're coming from there although that's a slight exaggeration considering how complex the structure of LSD is in comparison to this compound, as slapping a diethylamide moiety onto an ethyl and attaching all that to the amine of a PEA doesn't constitute a new chemical that's 'half and half' like a first-generation hybrid. Honestly this looks to me like a doodle I would do for the fun but silly reason of taking the diethylamide from acid and putting it into a PEA, like it belongs in the 'drawing random molecules' thread. Makes one wonder about replacing the diethylamide with a dimethylazetidide, a la LSZ. Surely the SAR isn't that directly analogous?

So, does this perhaps look intriguing? Again I don't know enough about SAR when it comes to compounds that are reasonably different from their relatives, which this definitely qualifies as, so if anybody has any insights they'd be interested to share that would be great.

That's all!

 

[sekio]

This is all predicted, though. Nobody has actually measured the affinity/activity of the hypothetical beast you have there in a real working biological system. To my knowledge nobody has even made the things. And of course, being a good ligand for a receptor doesn't mean it's a good drug.

Their QSAR model not including the benzyl-PEAs is not a surprise - this was published in 1999, well before Braden/Heim. The hemi-FLYs being predicted as high potency agonists is a good sign. On closer inspection, some shit doesn't make sense though - tryptamines and PEAs do not share the same binding site, for instance. And their model predicts a higher affinity for N-Me-DOM than plain DOM? Whutzzatabout?

That (amino)-(carbon spacer)-(amide) moiety reminds me of local anesthetics like procaine and lidocaine. I wonder if it would present toxicity problems.

Curiously, a couple closely related compounds were synthesized as analogs of LSD... for inhibiting pseudocholinesterase, though. Not tested in man.

 

[Deinonychus]

Aye, this is one of the things that is peculiar to me about this compound. The paper is old, yet it's never popped up on the market, and while its certainly an interesting idea, I'm not aware of close homology between tryptamines and phenethylamines, and especially not PEAs and lysergamides. Sure you can trace out the shape of a phenisopropylamine within a lysergamide, but you can see PEAs in a lot of different chemicals, which don't necessarily have anything in common.

What I wonder about really even more than just the peculiarities of this compound is what the specific relationship between length/size of n-substitution and activity level may be. It appears from Shulgin's work that short alkyl groups diminish the activity of psychedelic PEAs and amphetamines (I missed that N-Methyl-DOM nonsense, red flag, a lot) and that the activity seems to diminish with length. But yet certain forms of large n-substituents are not only active, but potently so. This compound could go either way, no way to know when it's been simulated but not actually made. Still it would be nice to have another data point there, especially since this isn't really anything like an NBOMe to try and elucidate whether there's a nice, neat pattern regarding length and size of the n-substituents.

Not to get too far off the dubious-molecule as topic, but I'd like to see how varying the length of the 'carbon spacer' between the PEA and the amide, or a PEA and its n-benzyl, will effect activity. Quite possibly the resulting compounds would just be the wrong shape to bind, being too big and floppy, or too short and stiff, but performing a few simulations in silico is much less resource intensive than actually making the things. Sure, there may be inaccuracies compared to actually assaying those chemicals but it is only a whim, I'm just curious how the shape of things on that end of the molecule affect binding affinity.

 

[NeuroPsyence]

Given that I'm the clown who started the thread mentioned in the OP, I figured I should chime in. Just time for one quick note now, but I'll be back.

Makes one wonder about replacing the diethylamide with a dimethylazetidide, a la LSZ. Surely the SAR isn't that directly analogous?

When bound to lysergic acid in the (S,S) configuration, the dimethylazetidide functional group causes the molecule to possess a a Ki value at 5-HT1a less than half of what the molecule exhibits with the diethylamide functional group (i.e. a significantly stronger binding at the receptor)! Given the powerful neuromodulatory effects resulting from 5-HT1a agonism (for instance, 5-HT1a antagonists have been shown to completely prevent the pro-social effects of MDMA), this could imply the potential to significantly alter the effects of the drug, even with comperable agonism at 5-HT2 receptors. Unfortunately, guesses as to how closely this established SAR for ergoline drugs would apply to the hypothetical compound discussed in this thread would, of course, be speculative.

 

[Deinonychus]

^^ Indeed, the Nichols paper on LSZ mentions that the diethyl moieties on the amide in LSD are quite likely oriented when bound to the receptor in such a way as to be almost exactly superimposable upon the dimethylazetidide group in LSZ. Keeping with the theme of how far the homology goes between LSD and this compound, which is a mouthful by the way and not easily abbreviated, I wonder whether the diethylamide would end up being oriented in a similar fashion.

My thinking is that it would not, because the conformational shape of LSD when bound is a function of the overall shape of the molecule, which is big, and compared to this compound fairly rigid. The shape of the aromatic ring here is pretty dissimilar, and it has electronegative substituents that have no close parallel in LSD, but then again this compound just strikes me as totally improbable, so for all we know there may be direct parallels between it and LSD. It's easily superimposed itself upon LSD, as Sekio demonstrated, but it's so much more floppy!

If there are direct parallels, the logical next step would be to explore various other substitutions, like the 3-pentylamide, methylisopropylamide, dimethylazetidide, etc. I wonder why this one hasn't ever gone past the theoretical level (that we know of?), it is certainly an interesting candidate for psychedelic action if just for no other reason that its structural peculiarity. Methodological errors in the original paper perhaps? That N-methyl-DOM > DOM binding affinity thing is not a friendly sign in that regard, I'm glad Sekio pointed that out.

Looking at it from the other side of things, the PEA side, I wonder also how that aromatic ring will function. I know that the 'main' ring in the case of the NBOMes is located differently relative to the receptor than in vanilla PEAs, and so it would be interesting to simulate this binding (2b is the only subtype to be structurally elucidated if I recall correctly?) to see how the location of the main ring and its methoxies compares to both ordinary PEAs and NBOMes.