QSAR studies say that an amphetamine like DOI coupled with a 3-[N-diethyl-1-(n-propanamide)] on the nitrogen makes a 5HT2a receptor agonist equipotent
to LSD.
how could the synthesis be accomplished, starting from the amphetamine?Furch - 13-3-2007 at 09:48
I would love to help you, but I don't understand what the molecule looks like. 3-[N-diethyl-1-(n-propanamide)] makes no sense to me... Can you perhaps
draw the molecule, or give me the SMILES code for it?stoichiometric_steve - 13-3-2007 at 11:17
the SMILES for the complete molecule would be
and the correct IUPAC name N,N-diethyl-3-(1-(4-iodo-2,5-dimethoxyphenyl)propan-2-ylamino)propanamide
CCN(CC)C(=O)CCNC(C)Cc1cc(OC)c(I)cc1OC
see attachment for picture.
[Edited on 13-3-2007 by stoichiometric_steve]
Nicodem - 13-3-2007 at 14:13
Quote:
Originally posted by stoichiometric_steve
QSAR studies say that an amphetamine like DOI coupled with a 3-[N-diethyl-1-(n-propanamide)] on the nitrogen makes a 5HT2a receptor agonist equipotent
to LSD.
Do you have in mind a quote from Nichols, in some old paper I just can not find at the moment, who once hypothesized this compounds might be more
potent 5-HT2A agonists than the N-unsubstituted parent 2,5-dimethoxy-4-X-phenylethylamines? His hypothesis was not based on QSAR, but plain good old
SAR (QSAR is completely useless for such predictions). If you have some other reference, please be a gentleman and provide it.
Anyway, now, years later when the super potent psychedelic N-(2-methoxybenzyl) phenylethylamine and tryptamine derivatives were discovered, part of
his hypothesis could be considered proven (2-methoxybenzyl isostere efficiently acts as the talked about alkylamide group at the receptor). But to my
knowledge the N-(CH2CH2CONEt2) substitution was never tried on an 5-HT2A agonist. Thus it is formally still just a hypothesis.
It should be possible to alkylate N-benzyl protected phenylethylamines with methyl acrylate, followed by hydrolysis, coupling with diethylamide and
debenzylation with H2/Pd-C. Perhaps it would be even possible to alkylate directly with N,N-diethyl acrylamide which is however considerably less
electrophilic than methyl acrylate. This would allow skipping the hydrolysis and coupling steps.stoichiometric_steve - 13-3-2007 at 22:23
According to the literature you are lucky in that:
a.) acrylamides are just electrophilic enough for the alkylation of amines;
b.) there are a couple of examples where primary amines were selectively monoalkylated with acrylamides.
Therefore, there is no need for amine benzylation to preform the secondary amine and you can use straight N,N-diethyl acrylamide for the
alkylation. This means the synthesis is a one step reaction from the appropriate phenylethylamine, though you need acrylic acid chloride and
diethylamine to prepare the required electrophile.
That paper (attached) looks a bit dull like most QSAR papers and it does not seam to give the credit to Nichols for the original suggestion of the
-CH2CH2CONEt2 substitution at the amine. However, I have to admit they were quite advanced with their interaction modeling considering that it is from
the year 1999 when Heim's 2-methoxybenzyl amine substitution was yet unknown. Yet, given that such an amide might be metabolically somewhat less
stabile and certainly much more hydrophilic, I would expect any such compound like you draw would be less potent than the N-(2-methoxybenzyl)
corresponding counterpart (the N-(2-methoxybenzyl)-2C-B is expected to be psychedelic at about 200 micrograms without considering the
metabolism, but more likely at about 500 micrograms given that benzylamines tend to be slowly oxidatively cleaved in vivo). Affinity, and
moreover predicted affinity is not all that is required for high potency. Besides metabolism, BBB penetrability and other pharmacodynamics you
need to consider also the possibility that the compound might be an antagonist. The N-(2-methoxybenzyl) compounds were luckily found to be
agonists, but their intrinsic activity is reduced in comparison to the parent compounds (for example, 2C-B has the intrinsic activity of 58% relative
to serotonin, N-(2-methoxybenzyl)-2C-B has it 38% while for N-(2-methoxybenzyl)-DOB it drops to 20% which nearly fits for a partial
agonism). The -CH2CH2CONEt2 group has much more "degrees of freedom" (less restricted in its conformational transformations) than the 2-methoxybenzyl
group, so I would expect an even more radical drop in the intrinsic activity (probably to the degree of a low efficiency partial agonism).
Yet a very interesting new type of compound to try and see…
hmmm, interesting. i never heard or read about the 2-methoxybenzylated stuff. have you got any good reads in that area? i'd highly appreciate that.
thanks in advance Nicodem - 14-3-2007 at 13:13
