Posted by chemist on July 7, 2004, at 16:59:27
In reply to Re: -acetam structure and GABA derivatives » chemist, posted by Larry Hoover on July 7, 2004, at 15:53:55
> > > > 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.
> > >
> > > Lar
> >
> > hello 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
>
> Whoa! It's going to take me a week to work through your post, line by line.
>
> Here's what I was referring to. joebob's original links included one to this abstract:
> http://www.biopsychiatry.com/aniracetam.htm
>
> Aniracetam enhances cortical dopamine and serotonin release via cholinergic and glutamatergic mechanisms in SHRSP
> by
> Shirane M, Nakamura K.
> CNS Supporting Laboratory,
> Nippon Roche Research Center,
> 200 Kajiwara, 247-8530,
> Kamakura, Japan
> Brain Res 2001 Oct 19;916(1-2):211-21
>
> ABSTRACT
> Aniracetam, a cognition enhancer, has been recently found to preferentially increase extracellular levels of dopamine (DA) and serotonin (5-HT) in the prefrontal cortex (PFC), basolateral amygdala and dorsal hippocampus of the mesocorticolimbic system in stroke-prone spontaneously hypertensive rats. In the present study, we aimed to identify actually active substances among aniracetam and its major metabolites and to clarify the mode of action in DA and 5-HT release in the PFC. Local perfusion of mecamylamine, a nicotinic acetylcholine (nACh) and N-methyl-D-aspartate (NMDA) receptor antagonist, into the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) completely blocked DA and 5-HT release, respectively, in the PFC elicited by orally administered aniracetam. The effects of aniracetam were mimicked by local perfusion of N-anisoyl--aminobutyric acid (N-anisoyl-GABA), one of the major metabolites of aniracetam, into the VTA and DRN. The cortical DA release induced by N-anisoyl-GABA applied to the VTA was also completely abolished by co-perfusion of mecamylamine. Additionally, when p-anisic acid, another metabolite of aniracetam, and N-anisoyl-GABA were locally perfused into the PFC, they induced DA and 5-HT release in the same region, respectively. These results indicate that aniracetam enhances DA and 5-HT release by mainly mediating the action of N-anisoyl-GABA that targets not only somatodendritic nACh and NMDA receptors but also presynaptic nACh receptors.
>
> For emphasis, I'm isolating this quotation from the abstract: "The effects of aniracetam were mimicked by local perfusion of N-anisoyl--aminobutyric acid (N-anisoyl-GABA), one of the major metabolites of aniracetam, into the VTA and DRN."
>
> On the same page is a link to aniracetam's structure: http://www.biopsychiatry.com/aniracetam/index.html
>
> If the upper ring opens between the carboxyl and the ring nitrogen, you get a substituted GABA. (I'm going to presume that the substituted benzoate moiety goes by the trivial name of anisoyl.)
>
> Here's the structure for oxiracetam: http://www.biopsychiatry.com/oxiracetam/index.html
>
> If the ring opens, you get hydroxylated, N-substituted GABA.
>
> Here's the structure for pramiracetam:
> http://www.biopsychiatry.com/pramiracetam/index.html
>
> Open the ring, and.....I'm sure that you're getting the gist of my speculation....
>
> Lar
>
yup, got it.....and even have done some QSAR/QSPR and MD stuff with the compounds you mention :)
what i hadn't come across was what the metabolites were and what they looked like, and this was merely because i was not aware of any GABA-like actvity in re: neuroprotection. but it makes sense from the ring cleavage point of view, and it certainly makes sense with the glutamate/aspartate stuff.....more anon, all the best, chemist
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thread:358292
URL: http://www.dr-bob.org/babble/alter/20040613/msgs/363800.html