![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 4 to 28 of 28. Go back in thread:
Posted by chemist on June 21, 2004, at 9:57:09
In reply to chemist........you may also be able to comment, posted by joebob on June 20, 2004, at 11:05:09
> on this and here's some techno stuff to give you a thrill :}
>
> http://www.cellnucleus.com/phosH3ser28.htm
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> http://www.cellnucleus.com/phosH3ser10.htm
>
> http://www.drdebe.com/Serine.htm
hey joebob, i am skeptical of the phosphoserine, mainly because of the 22 manuscripts sitting in my folder on my desk - all having to do with nootropics/drugs that are neuroprotective - don't mention it at all. if you want references, let me know, i'll type 'em in. fyi, your piracetam is just fine, although you might check out Manetti et al., J. Med. Chem. 43:1969-1974 (2000) as well as Camps et al., J. Med. Chem. 43:4657-4666 (2000). most of the literature i have is from the 1990s, just fyi. do let me know if you would like some refs in addition to those above...all the best, chemist
Posted by joebob on June 21, 2004, at 11:45:33
In reply to Re: chemist........you may also be able to comment » joebob, posted by chemist on June 21, 2004, at 9:57:09
the moment..
i wasn't able to pull up the citations you mention, but i basically want to know what you think of aniracetam and picmalion and Pyritinol...i am considering adding these as suppsi am wanting to drink and smoke less, or not at all, and will power ain't an option at the moment
i am also experiencing some spotty memory and lack of focus
you are only the second person i have been able to find who may have hard info on nootropics...the first was james south
i much appreciate any help/info/advice you can offer....but my biochem expertise is nil and it has been 30 years since chem or bio classes for me
thanks so much
joebob
Posted by Larry Hoover on June 21, 2004, at 12:17:18
In reply to larry hoover...can you comment on this, posted by joebob on June 20, 2004, at 10:29:34
> i use lex and depakote and supps
> i drink and smoke (organic tobacco)
> i use a lot of supps when time,money and motivation allow..........and am now getting interested in nootropics again
> have had some piracetam around for a long time and now am using it again, and like it a lot
>
> thanks
> joebobI'll come back to you....gotta run...
Posted by linkadge on June 21, 2004, at 13:02:34
In reply to Re: larry hoover...can you comment on this » joebob, posted by Larry Hoover on June 21, 2004, at 12:17:18
From what I hear kava kava is one of the best herbs to beat smoking and drinking. St. John's wort and Ginkgo may also be of some use.
Kava and ginkgo are good for the memory as well
Linkadge
Posted by chemist on June 21, 2004, at 20:38:10
In reply to cool.....it is nootropics i am interested in at, posted by joebob on June 21, 2004, at 11:45:33
> the moment..
> i wasn't able to pull up the citations you mention, but i basically want to know what you think of aniracetam and picmalion and Pyritinol...i am considering adding these as supps
>
> i am wanting to drink and smoke less, or not at all, and will power ain't an option at the moment
>
> i am also experiencing some spotty memory and lack of focus
>
> you are only the second person i have been able to find who may have hard info on nootropics...the first was james south
>
> i much appreciate any help/info/advice you can offer....but my biochem expertise is nil and it has been 30 years since chem or bio classes for me
>
> thanks so much
> joebobhey joebob.....i came up empty on picmalion: any other name or maybe a typo? (i am guilty of typos all the time). your piracetam is fine, but there is indication the nebracetam is 1000 times more potent. also, this compound - as well as aniracetam - reversed amnesia whether scopoloamine induced, antagonism of neuronal nicotine receptors (mecamylamine), agonism of GABA_{B} and the alpha_{2} agionist clonidine. get back to me on the mystery drug, would you? as for pyritinol, i'd stay away, as i found a couple of abstracts that indicate liver damage or pancreatitis following pyritinol.......hope this helps, and all the best, chemist
Posted by chemist on June 21, 2004, at 20:47:42
In reply to Re: larry hoover...can you comment on this, posted by linkadge on June 21, 2004, at 13:02:34
> From what I hear kava kava is one of the best herbs to beat smoking and drinking. St. John's wort and Ginkgo may also be of some use.
>
>
> Kava and ginkgo are good for the memory as well
>
>
> Linkadge
hello there, chemist here....please see ``A pilot trial of piracetam and ginko biloba for the tratement of cocaine dependence,'' Kampman et al., Addictive Behaviors 28:437-448 (2003). i quote: ``Ginko biloba was not superior to placebo [my note: this was a double-blind, 10-week, placebo-controlled study] in any outcome measure. Piracetam was associated with more cocaine use and lower CGI scores compared to placebo.'' the crux was that nootropics such as piracetam and ginko biloba could induce cognitave function in cocaine-dependent patients (N=44) and reduce relapse. i realize it's only one data point, and the authors do point to flaws, but the indication that nootropics for addictive behavior submission appear spotty.....as for kava and st. john's wort, the jury is out: kava has anxiolytic properties but is not a nootropic....all the best, chemist
Posted by joebob on June 21, 2004, at 22:21:49
In reply to Re: cool.....it is nootropics i am interested in at » joebob, posted by chemist on June 21, 2004, at 20:38:10
Posted by linkadge on June 22, 2004, at 13:06:57
In reply to Re: larry hoover...can you comment on this » linkadge, posted by chemist on June 21, 2004, at 20:47:42
I would definately say that cocaine is a much more potent stimulant than tobacco is. I do not suppose that ginkgo could even come close to reducing the cocaine craving in the heavy users.
Kava is an anxiolitic but also a potent MAO-B inhibitor. From what I hear more potent than Ginkgo and SJW - similar to smoking. It does have nootropic properties. Let us remember that GABA potentiation has nootropic properties.
Ginkgo has been shown to be of some use to smoking ceasation, because it does have a mild dopimanergic action.
The reason I suggest Kava is because MAO-B action would mimic cigarettes and GABA action would mimic alchohol.
I know a friend that quit both smoking and drinking with Kava. It may not be a long term solution however, since it may casue hepatotoxicity, (the jury is still out on that one)
Linkadge
Posted by chemist on June 22, 2004, at 15:37:24
In reply to on the contrary, posted by linkadge on June 22, 2004, at 13:06:57
hello the, chemist here...my comments/questions delineated by ***
> I would definately say that cocaine is a much more potent stimulant than tobacco is. I do not suppose that ginkgo could even come close to reducing the cocaine craving in the heavy users.
*** if you look at the LD_{50} for cocaine hydrochloride and nicotine, you will find that on a mg/kg basis (i.v.), cocaine is about 50 times less likely to cause death than nicotine ***
>
> Kava is an anxiolitic but also a potent MAO-B inhibitor. From what I hear more potent than Ginkgo and SJW - similar to smoking. It does have nootropic properties. Let us remember that GABA potentiation has nootropic properties.*** the component(s) you are referring to as potent MAO-B inhibitors isolated from kava kava were from one study that was done in vitro. the K_{i}s of the strongest 2 component was in the sub-micromolar to micromolar range. a potent inhibitor binds in (at least) the nanomolar to sub-nanomolar range. how is taking kava kava ``similar to smoking?'' any references would be appreciated. also, which component of kava kava are you referring to when you implicate the GABAnergic potentiation? any references are appreciated, because i am unaware of direct GABA modulation by binding to the BZ site (although there is weak affinity for GABA_{A}), rather, there are ways to do so by interaction of nootropics with AMPA. i assume you are talking about the aspartate/glutamate pathway, but please clarify. the nootropic properties of kava kava are from methysticin, but unfortunately, this component exhibits the greatest hepatic cyctotoxicity of the P450 class of isoenzymes. ***
>
> Ginkgo has been shown to be of some use to smoking ceasation, because it does have a mild dopimanergic action.*** can you provide any references that implicate binding of nicotine to neuronal nicotine receptors (alpha_{7} or alpha_{4}beta_{2} substypes) followed by dopanergic agonism/antagonism? many thanks! *****
>
> The reason I suggest Kava is because MAO-B action would mimic cigarettes and GABA action would mimic alchohol.*** again, how does MAO-B action ``mimic cigarettes?'' could you please clarify? i am unaware of any monoamineoxidase inhibition - reversible or not - by nicotine. thanks! ****
>
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> I know a friend that quit both smoking and drinking with Kava. It may not be a long term solution however, since it may casue hepatotoxicity, (the jury is still out on that one)
>
>
**** the jury is in: kava extracts were banned in the EU and Canada in january, 2003 thanks to 11 cases of hepatic failure (4 deaths resultant) and, according to ``Kava kava: examining new reports of toxicity,'' Toxicology Letters 150:85-96 (2004), there are a ``a total of 78 cases of hepatotoxicity reputedly linked to kava ingestion,'' also for reasons i cannot understand, the author concludes that the risk-to-benefit ratio remains good compared to other anxiolytics. in an abstract from Integ. Cancer Ther 3:128-148 (2004), the phrase ``Studies of better-known herbal sedatives, notably valarien and kava, showed moderate evidence for both safety and efficacy for valerian while revealing disturbing toxicity concerns for kava.'' there is evidence (in vitro) to support moderate to little toxicity (Planta Med. 70:289-292, 2004); that pipermethystine ``is capable of causing cell death, probably in part by disrupting mitochondrial function'' (Toxicol. Sci. 79:106-111, 2004); and there is evidence that hepatotoxicity is reversible. still, i'm not taking my chances.....all the best, chemist ******* and please do forward references in re: the connection with nicotine and MAO inhibition? many thanks, chemist *******
> Linkadge
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Posted by linkadge on June 22, 2004, at 17:57:00
In reply to Re: on the contrary » linkadge, posted by chemist on June 22, 2004, at 15:37:24
MAOB properties
---------------
http://biopsychiatry.com/kavakava.htm
Argument about the valitity of liver toxicity
---------------------------------------------
http://biopsychiatry.com/kavasaferisk.htmNoting that many of the claimed cases involved the concurrent usage of conventional anxiolitics.
Reference for kava/gaba interaction
-----------------------------------
Jussofie A, Schmiz A, Hiemke C. Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology. 1994;116:469–474
Kava's Role in Cognition / Nootropic properties
------------------------Enhanced cognitive performance and cheerful mood by standardized extracts of Piper methysticum (Kava-kava).
The acute effects of the herbal anxiolytic Kava-kava (Piper methysticum G. Forster) on emotional reactivity and cognitive performance were investigated in a double-blind randomized placebo-controlled trial involving healthy volunteers. Subjects' reports of mood change were assessed with the state-trait-cheerfulness-inventory, which measures the three concepts of cheerfulness, seriousness and bad mood as both traits and states. Cognitive performance was examined with the Sperling partial report and the Sternberg item recognition task, which were used as an index for visual attention and short-term memory processing. The intake of a single dose of Kava extract (300 mg; p.o.) led to an increase in state cheerfulness, while the phytopharmacon did not influence state seriousness and bad mood. The mood-elevating effects of Kava were most prominent in trait cheerful subjects, indicating that trait cheerfulness moderated the drug-induced increase in cheerful mood. Furthermore, Kava improved the accuracy and the speed of performing the partial report and the item recognition task, indicative of a beneficial
effect of the phytopharmacon on visual attention and short-term memory retrieval, respectively. Thus, unlike conventional benzodiazepine-type anxiolytics, which tend to impair cognitive performance and to increase the occurrence of negative affective states, Kava is a potent anxiolytic agent, which, additionally, can facilitate cognitive functioning and can increase positive affectivity related to exhilaration.
Posted by chemist on June 22, 2004, at 18:46:08
In reply to Re: on the contrary, posted by linkadge on June 22, 2004, at 17:57:00
> MAOB properties
> ---------------
> http://biopsychiatry.com/kavakava.htm
>
>
> Argument about the valitity of liver toxicity
> ---------------------------------------------
> http://biopsychiatry.com/kavasaferisk.htm
>
> Noting that many of the claimed cases involved the concurrent usage of conventional anxiolitics.
>
>
> Reference for kava/gaba interaction
> -----------------------------------
> Jussofie A, Schmiz A, Hiemke C. Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology. 1994;116:469–474
>
>
> Kava's Role in Cognition / Nootropic properties
> ------------------------
>
> Enhanced cognitive performance and cheerful mood by standardized extracts of Piper methysticum (Kava-kava).
>
> The acute effects of the herbal anxiolytic Kava-kava (Piper methysticum G. Forster) on emotional reactivity and cognitive performance were investigated in a double-blind randomized placebo-controlled trial involving healthy volunteers. Subjects' reports of mood change were assessed with the state-trait-cheerfulness-inventory, which measures the three concepts of cheerfulness, seriousness and bad mood as both traits and states. Cognitive performance was examined with the Sperling partial report and the Sternberg item recognition task, which were used as an index for visual attention and short-term memory processing. The intake of a single dose of Kava extract (300 mg; p.o.) led to an increase in state cheerfulness, while the phytopharmacon did not influence state seriousness and bad mood. The mood-elevating effects of Kava were most prominent in trait cheerful subjects, indicating that trait cheerfulness moderated the drug-induced increase in cheerful mood. Furthermore, Kava improved the accuracy and the speed of performing the partial report and the item recognition task, indicative of a beneficial
> effect of the phytopharmacon on visual attention and short-term memory retrieval, respectively. Thus, unlike conventional benzodiazepine-type anxiolytics, which tend to impair cognitive performance and to increase the occurrence of negative affective states, Kava is a potent anxiolytic agent, which, additionally, can facilitate cognitive functioning and can increase positive affectivity related to exhilaration.
>
>
thanks, i should have been more specific in re: peer-review, refereed pubs (in reference to the websites to which your point). i will mention i am highly skeptical of xxx, because from their home page, i was able to get a list of offshore/Mexican pharmacies (click on xxx). plus, while on the same page, you can get to xxx, all from xxx. my favorite quote - right on the home page is xxx. this source is, in my opinion, lacking. in so many ways.the abstract about the MAOB connection is the one i referenced with sub-micromolar K_{i}. just wondering why there are no drugs being marketed based on kave pyrones for MAOIs.....
the gaba/kava pub. mentions modulation of the GABA_{A} muscimol binding sites, not GABA sites, and not GABA. hence, no connection in this pub.
the abstract about cheerfulness assiciated with kava is one i came across on pubmed and dismissed because the authors conclude that because a person who is exhilirated due to the psychotropic effects of kava can recall images and exhibits less short-term memory loss, hardly indicators of nootropic efficacy. we are talking about long-term neurodegerenative effects. kava kava in not on the radar of those of us who work on therapies for Alzheimer's, i can assure you....all the best, chemist
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Posted by linkadge on June 22, 2004, at 19:50:52
In reply to Re: on the contrary » linkadge, posted by chemist on June 22, 2004, at 18:46:08
Well, to be perfectly blunt, you can look at it any way you want.
There are numerous reports of nootropic efficacy of kava. Nootropic is any simply any drug that can enhance mental function. Kava fits this definition. Anyone who has ingested kava can attest to this. Weather it has utility in Alzheimers is another issue.Linkadge
Posted by Questionmark on June 23, 2004, at 17:05:36
In reply to Re: on the contrary » linkadge, posted by chemist on June 22, 2004, at 18:46:08
There might not be any research to support this, but if you look at many of the native peoples of certain South American countries you will find that they chew coca leaves every day-- like we Americans drink coffee-- and their health is essentially fine except for their decayed tooth enamel. Biopsychiatry is definitely a biased website, but i think they have a lot of good, factual information about psychopharmacology & what not. And they do provide a great deal of research (abstracts at least), which you cannot just throw out the window.
But i'm not sure what to think about Kava's MAO-B inhibiting properties and Ginkgo's dopaminergic properties. I.e., i'm not sure if the overall research supports this or not.
Posted by linkadge on June 23, 2004, at 18:33:15
In reply to Re: on the contrary, posted by Questionmark on June 23, 2004, at 17:05:36
I agree that the biopsychiatry page is pretty much a cultish website, but you are right that the abstracts are abstracts.
Give kava a try for yourself. Do some simple memory games. It really is a powerpunch. Of all the herbals, I'm beginning to think this one was partially taken off the market because of its abuse potential:)
Linkadge
Posted by KaraS on June 23, 2004, at 20:11:55
In reply to Re: on the contrary, posted by linkadge on June 23, 2004, at 18:33:15
I don't think that Biopscyhiatry is a cult site. That's much too strong a word for it. It's a site with a definite point of view which it backs up with the abstracts. I've gotten a lot of good information from there. You just have to keep in mind where the author is coming from.
As for Kava, I've read so many different things about its safety. Some have said that the studies showing it to be unsafe have used parts of the plant that shouldn't be used. They claim that if you have pure quality product that it's perfectly safe. Even conservative supplement advocate Dr. Ray Sahelian still takes it. But there's too much uncertainty about it for my taste. I'd rather be safe than sorry.
Posted by linkadge on June 24, 2004, at 10:03:02
In reply to Re: on the contrary » linkadge, posted by KaraS on June 23, 2004, at 20:11:55
Really only kidding with the word "cultish". You are right, there is too much uncertainty to use kava on a regular basis, but herbs like kava only come around once in a lifetime. It really does need to be researched more rigerously.
Linkadge
Posted by Dr. Bob on June 25, 2004, at 14:32:05
In reply to Re: on the contrary » linkadge, posted by chemist on June 22, 2004, at 18:46:08
> i am highly skeptical of xxx, because from their home page, i was able to get a list of offshore/Mexican pharmacies (click on xxx). plus, while on the same page, you can get to xxx, all from xxx. my favorite quote - right on the home page is xxx. this source is, in my opinion, lacking. in so many ways.
The idea here is not to exchange information that could be used to import into the US prescription medication without a prescription:
http://www.dr-bob.org/babble/faq.html#illegal
So please don't post the address of or quote from pages like that. Thanks,
Bob
Posted by chemist on June 25, 2004, at 15:28:24
In reply to Re: medication without a prescription » chemist, posted by Dr. Bob on June 25, 2004, at 14:32:05
will do. apologies. it was - as you know - part of my reply questioning the validity of the site named by the poster. again, apologies. all the best, chemist
Posted by KaraS on June 27, 2004, at 19:12:51
In reply to Re: on the contrary, posted by linkadge on June 24, 2004, at 10:03:02
Is Kava really that good???? Maybe I should try it at least once!
Posted by Dr. Bob on June 28, 2004, at 6:49:56
In reply to Re: medication without a prescription » Dr. Bob, posted by chemist on June 25, 2004, at 15:28:24
Posted by linkadge on June 29, 2004, at 13:14:02
In reply to Re: thanks (nm) » chemist, posted by Dr. Bob on June 28, 2004, at 6:49:56
Kava is good.
Posted by Larry Hoover on July 3, 2004, at 11:02:48
In reply to oops.....forgot the links and, posted by joebob on June 20, 2004, at 10:42:04
> 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.htmFascinating. 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.htmlInteresting 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
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
Posted by Larry Hoover on July 7, 2004, at 15:53:55
In reply to Re: oops.....forgot the links and » Larry Hoover, posted by chemist on July 7, 2004, at 10:36:41
> > > 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, chemistWhoa! 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.htmAniracetam 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):211-21ABSTRACT
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.htmlOpen the ring, and.....I'm sure that you're getting the gist of my speculation....
Lar
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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