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Re: Question for chemist on benzos (experts) + MORE. jlbl2l

Posted by chemist on April 22, 2004, at 20:20:04

In reply to Question for chemist on benzos (experts) + MORE., posted by jlbl2l on April 22, 2004, at 3:21:24

> chemist,
> you seem quite knowledgable on many medicines, (and I am trying to become a qualified expert myself) so I thought I'd ask some questions or re-affirm some things that I may be wrong at. I may append more to this post later and I would like to continue discussion of other things if I find this helpful.
> First, Klonopin and Xanax (in general) have both roughly the same equivalency at dosage of 0.5mg, however xanax has a much earlier onset of action and hit's a slightly different subset of gaba-a receptors creating the quicker and more "high" feeling in most people.
*** the reason xanax is different from any other benzodiazepine is that it is NOT a 1,4-substituted (or 1,5, for that matter, such as clobazam) benzodiazepene: it is a triazolobenzodiazepene, and the addition of the triazolo group would account for the anti-depressant effects of xanax. also, xanax and the benzos all hit GABA_{A}, and in particular, bind between the alpha and gamma sub-units. finally, there are compelling evidence that the benzodiazepine binding in GABA_{A} is between subunits alpha1 and gamma 2 and that the most likely heteropentameric arrangement of GABA_{A} for greatest agonism/antagonism/inhibition is the (alpha1)_{2}(beta2)_{2}gamma1 stoiciometry.****
It also seems to be more of a relaxant probably hitting what, i think c subtype of the gaba-a - is for muscle relaxant properaties?
*** there is no such beast as the c subtype of GABA_{A}. GABA_{B} and GABA_{C} are the other subtypes. as for muscle-relaxant properties related to GABA_{C}, all ligands with sub-micromolar K_{i} for this subtype are associated with cognitive function and, so a lesser degree, occular function.*****
Anyways, Xanax metabolies into oxazepam , like almost every benzodiapine, correct?
*** why would it? active metabolites of diazepam, for instance, are oxazepam and desmethyldiazepam and (i cannot recall if this is correct) nordiazepam. xanax is metabolized to (active) alpha-hydroxy alprazolam and 4-hydroxy alprazolam; another triazolobenzodiazepene, adinazolam, is metabolized to N-desmethyladinazolam, estazolam, and alpha-hydroxy adinazolam. want to do drug tests for chlorazepate? look for desmethyldiazepam. clonazepam goes to 7-amino-clonazepam and 7-acetamidoclonazepam. nordiazepam goes to oxazepam, but oxazepam can be readily hydrolyzed.***
So when I take Ativan, or Xanax, or (another common benzo (not klonopin though) it is actually just oxazepam that i would be taking, correct? In most drug tests, they usually only test for oxazepam (unless special tests are ordered) since almost all benzos metabolize into it.
*** nope. see above, and extensive literature on what forensic analysis for the presence of benzodiazepenes is all about. it's NOT about looking for oxazepam.....*****
Anyways, My comparison here is Klonopin vs Xanax and the tolerance vs the 2 and effectiveness vs the two and the metabolites vs the two. I am aware Klonopin converts uniquely (amoung only a few others benzos) to its specific form of 7-amino-clonazepam rather than most benzos which convert to oxazepam.
*** again, misinformed. xanax isn't even a benzodiazepine, and comparing the (different) metabolites for your ``dose equivalence'' is no good. a hydrolyzed species will stay in the brain longer - hydrophilic moiety prevents crossing the blood/brain barrier too soon - than an aminated one, such as the 7-amino derivative of clonazepam. xanax is way mre lipophilic than clonazepam, thus the earlier onset of action, as this crosses the blood/brain barrier (and i note that the hydroxy metabolites have a slower time getting across said boundary)****
Question -> Does this effect the feeling of the benzo in any way? I know this would effect a drug test, but would it convert AFTER or BEFORE the binding, do you understand what I am saying?
*** i assume you are referring to what i noted above, i.e., what species are left after your liver has done the round of metabolism. you will have unchanged parent drug and active/inactive metabolites. the ease at which any of these (and their potenticies) cross the blood/brain barrier is the first step. then, binding to (almost exclusively) the specific GABA_{A} receptor, and the binding affinities will be different, although a low binding affinity can be offset by a longer residence time of active metabolite buildup****
Second thing, is that Klonopin seems to also have an antidepressant effect like xanax, but it wears off after you gain tolerance. It seems this has been established through interactions through 5HTP/SEROTONIN interactions.
***tolerance can and will be achieved for both drugs. as for serotonin: i am sure you are aware of the structural and functional homology of the ligand-gated ion channels such as acetylcholine binding protein, the neuronal nicotine receptor, GABA receptors, and of course, 5-HT (in particular, the 4 subtypes of 5-HT_{1}). GABA_{B} - which is coupled to calcium and potassium flux as opposed to GABA_{A} and GABA_{C} (chloride flux) - might work in a synergistic fashion, although i remain ignorant of the mechanism. could be cAMP levels for polarizing the channel? i don't know..****
Can you explain how benzos are helping in this (speicfically), and why klonopin eventually stop's working, while xanax, doesn't seem to from what i have heard. Could it be the half life factor; in that its harder to gain tolerance to xanax? Also, For Klonopin, What Gaba-A subtype receptors does it hit the most.
****i think i have pretty thoroughly exhausted how benzos work, but here we go: take a benzo. some parent drug remains and some metabolites are formed (active/inactive). transport across blood/brain barrier. bind between the alpha1 and gamma2 subunits of the GABA type A receptor. upon ligand binding, chloride flux ensues, ligang-gated channel opens, GABA reuptake inhibited, inhibitory effects felt. as for subreceptors for klonopin: if you are a benzodiazepene it is imperative that you bind at the junction of an alpha and gamma subunit of the GABA receptor.***
Obviously, we know it hits the anxiolytic subset and the (hypnotic areas-as most benzos do) but it doesnt do much for muscles (for me at least).
***but you said so above, in your post at the beginning, and you implicated the (non-existant) c subtype of GABA_{A}. as for ``the hypnotic set,'' it's a set of 1: the alpha1.*****
I guess this is why it is an ideal agent for social phobia, esp the long half life and anti-d effects. Can you just "babble" for me a bit (feel free to go into very,VERY much chemical and technical detail such as ion channel, calicum influx, potassium blockage etc.. and such as I understand most of this, I study neuropharmcology and neurochemistry but from your posts it seems you could aid in my knowledge. Also I am HIGHLY interested in pregablin and neurontin ( I know how they generally work, but I would like to know a lot more on why they aren't scheled subtances
** do you mean why aren't they scheduled? first of all, they have to have shown through phase IV and post-marketing (not so in the ill-fated pregablin attempt, though...) that there is evidence for addiction potential. second, gabapentin is a GABA agonist, but it sure isn't prescribed for anxiety as much as for peripheral neuropathy, for instance, or for add-on therapy for epilepsy. these target populations are likely not to be the kind of crowd involved in classical drug-seeking behavior....*****
LOL (in your opinion). I mean, they work through calcium influx mechinisms correct? but they work throughout the entire body, not just the brain , so they work at all levels , hence the benefit to neurpathic pain and fibro patients etc.., those substances interest me the most actually because of the possibily of no downregulation or upregulation, though, i know thats probably impossible. Thoughts on topamax would be nice as well, especially its glutamate blocking properaties (and where it blocks it to IE NMDA ?), and its whole "brain" level of raising gaba and how it does this and what does it do
***topiramate antagonizes the AMPA/kainate glutamate receptor, not the NMDA one.also, topirimate inhibits sodium channels and activates calcium channels. the binding of topirimate is a myystery to me, i suspect the sulfamate group is key and that the interaction is at AMPA/ for neuropeptide Y, no evidence of of interaction. as for *whole* brain GABA flood, could be the inhibition of glutamate release or regulation of GABA transmission...again, i don't know....*****
with NP-Y and the other factors - I know theres 2 other hormone like factors it effects that are related to sleep, eating and behavior. Anyways.
***NP-Y, proopiomelanocortin system, and corticotropin-releasing hormone. as for NP-Y, no interaction with these other 2. hope i passed your quiz. when i earned my ph.d. several years ago i used to have students like you....all the best, and take your meds......chemist
Thanks again
> Thanks.
> jlbl2l
> neuropsychopharmacology researcher




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