Posted by chemist on July 7, 2004, at 10:36:41
In reply to Re: oops.....forgot the links and » joebob, posted by Larry Hoover on July 3, 2004, at 11:02:48
> > then had a crash...
> > maybe dr bob should start a board for xp users with strange os problems that can lead to confusion and anxiety :)
> >
> > anyhow heres the stuff i would like your commments on if you have the time and interest
> >
> > http://www.biopsychiatry.com/aniracetam.htm
>
> Fascinating. It would appear that the -acetams, as a class, have a similar chemistry. The -acetam ring opens, and what is left is an N-substituted GABA. I hope chemist comes back into this discussion. That is his realm.
>
> > and
> >
> > http://lifeextensionvitamins.com/serphosser.html
>
> Interesting that they distinguish between the effects of phosphatidyl serine and phosphated serine. It is quite true that the fatty acids in the phosphatide are subject to oxidative degradation (rancidity).
>
> These are both good leaping-off points for further study. I shall have to come back to this all after some research and cogitation.
>
> Larhello there, chemist here...sorry for being out of touch...the pubs i have in my files (about 20 or so) are mostly roeated to synthesis and characterization of nootropics. let me ramble on a bit...first off, the common theme for almost every nootropic is the presence of a 2-oxopyrrolidine structure. almost every derivative that is found to be active that is not similar to the piracetam structure (e.g. AChE/BChE inhibitor analouges of huperzine A, see j. med. chem. 38:3645-3651, 1995) must be substituted in at least one nitrogen position. in this case, galanthamine, E-2020 and huperzine A are all selective for AChE over BChE and are reversible inhibitors of AChE that do not acetylate the active site. in the compounds where the 2-oxopyrrolidine ring is absent, it appears that substitution of a primary amine and/or pyridinone nitrogen must be done to produce a drug with sub-micromolar binding affinity. it gets messier. so far, we've been looking at AChE (reversible) inhibition. however, there's the NMDA bit (and yes, also KA and AMPA). competive/non-competitive NMDA antagonists are targeted in cell death via cerebral ischemia (see j. med. chem. 37:3008-3015, 1994, e.g.): here, a series of 2-amino-alpha-thienylbenzeneethanamines was studied, and the best neuroprotectant was a derivative that was methylated at - you guessed - a primary amine. in this pub, the results were generalized to a small alkyl substituent on the alpha-nitrogen as well as a substitution in the ortho position of the thiophene ring, so looking at ortho directors or para/meta deactivators. in keeping with the ischemia theme, there are a host of adenosine receptor (sub-receptor, really) agonists (j. med. chem 46:3775-3777, 2003; j. med. chem. 46:794-809, 2003; j. med. chem 36:2508-2518, 1993, e.g.). in the first of the 3 refs, they look at sub-nM affinities of (naturally) N-substituted 4'-thio analogues of Cl-IB-MECA, which had a K_{i} of about 1 nM for the A_{3} subreceptor. this is interesting in that by halogenating IB-MECA, K_{i} dropped and selectivity for A_{3} over A_{1} and A_{2A} increased. the now, IB-MECA's main skeleton is a purine, as you would expect for an adenosine analogue. the chloro substituent in between the 2 nitrogens in the pyrimidine, and the primary amine is meta to the Cl, so this makes sense as far as enhancing binding affinity (the amino group here - as in the case of the NMDA inhibitors - is methylated). no ring cleavage so far, from what i have, but again, if i were to look, i'd go for an activated ortho/para position, hence the chloro. the second 2 pubs deal with A_{1} selective antagonists, and are xanthine derivatives, so you have a purine-based skeleton including a doubly-bound oxygen, making these compounds (in the QSAR/QPER sense) similar to the A_{3} selective antagonists and the ``traditional'' piracetam-like nootropics. they get into K_{ow} being a factor in retention of several of the analogues with similar K_{i}'s, so again, we are looking at substituents on the ring(s) and elsewhere. okay, enough for now. the ring cleavage you mention is certainly probable given the chemistry of all these compounds. however, i have not done my homework on what literature is out there in terms of assaying the by-products of degradation. more later, and all the best, chemist
poster:chemist
thread:358292
URL: http://www.dr-bob.org/babble/alter/20040613/msgs/363705.html