Carisoprodol: Psychopharmacology-dynamics help!

[negrogesic]

I am curious as to ideas or knowledge of carisoprodol psychopharmacology. Even my 1500 page Med-school "Textbook of Psychopharmacology (Schatzberg, Nemeroff, 4th edition-2009)" it makes only passing reference to carbamates and their activity.

My smaller, "Manual of Clinical Psychopharmacology" (Schatzberg,Cole,De Batista-4th edition-2005) does address it, however very superficially. It does not address carisoprodol directly, only its "pro-drug", meprobamate. It states the following:

Meprobamate does not affect benzodiazepine or GABA receptors. It seems to act by potentiating the action of endogenously released adenosine; it blocks reuptake of adenosine......

the same text states:

Its [meprobamate] antianxiety effects in laboratory animals can be blocked by naloxone

The first notion is certainly false, yet this manual is CURRENTLY used in clinical practice, and such statements are dangerous in the even of over dose. It is know to be a direct modulator of GABAa receptor sites (did not look at the *ucking structure?), however its activity (carisopridol) is purportedly not reversed using flumazenil, yet is reversed by barb-antagonists (from what I recall, bemigride or maybe megimide, I believe its structure is, simply put, something like fl-ethyl-fl-methylglutarimide or more specificaly 3[?/3]-ethyl-fl-methylglutarimide).

And then the second notion that its anxiolytic properties (meprobamate) are reversed by naloxone. So what, it MOR affinity? Where are the numbers? Its obviously not in the nM range, and I only see "downsteam" opioidergic properties, but I am not a doctor of medicinal chemistry, and QSAR programs pump out all sorts of weird shit.

2D

3D

In any case, anyone who has taken both miltown or pure meprobamate will realize carisopridol is no mere pro-drug, yes a unknown part of its activity can be attributed to its meprobamate metabolite, but again, it is distinctly (subjectively) different. Can someone people elaborate.

I believe it has been show affinity to glycine a1, and god knows what else (Kainate receptors or ligand-gated ion channeled NMDA sites). I have done the receptors but please, enlighten me. Physicians here in the US have a terrible understand about clinical pharm in general, but focus so much on anatomy, over and over. As a soon to be medical doctor, with supposed expertise in the highly competitive specialty of anesthesia (scary thought I know, no plans to practice) I feel dangerously ignorant, but am more concerned about my oblivious classmates. Propofol has made things easier; ive never killed a dog or human as an anesthetist . I do not have a PhD, but I feel like I should have or need to obtain one or more to be truly informed. Don't even get me started on tramadol, but at least there is better data despite being relatively new compound.

There is endless of info on the pharmacokinetics of carisoprodol, but no consensus on they dynamics/mechanism.


I know there are highly educated and intelligent people who view this forum, please elucidate and enlighten me.

 

[negrogesic]

Note: sorry for the spelling and typographical errors, this "android" is a bitch, but then again, I rarely proofread and speak informally.

 

[negrogesic]

Here is an abstract and a link to the full text of a recent and somewhat comprehensive study published in JPET (better known as ASPET, which is NIH funded) in 2009 . Issue is, its not conclusive and I haven't seen similar studies. Basically, they find it to be an allosteric modulator of GABA-A, but not at any BZD sites but has activity at "GABA-Ars", again not mentioned in any of my textbooks. They kind of lost me there, again, I have no PhDs. I am assuming subunit α1β1γ2 is the site (which I thought was GBL's or other lactones site, aside from its GHB-GABA-B properties) , but the article only raises more questions.

So, what I got from it, and I may be very wrong, is that it is a dose-dependent allosteric modulator of GABA-A, no affinity for BZD sites, and is "barbiturate-like" agonist (and partial agonist or antagonist at dose?), but they are not concluding that its mechanism is that of barbs. Their study shows carisoprodol to be MORE potent than its supposed active metabolite, meprobamate.

I understand its beyond the scope of the study, but what about GABA-B, GABA-C and the study which shows reversal of anxiolysis with naloxone (thus; what are the opioid implications and is it possible that there is true potentiation of codeine etc, similar in mechanism but not as powerful as glutethimide?) .

I need a MCB or biochemist who knows this area. Any conjecture would help, but for me its just a shot in the dark.

Carisoprodol is a frequently prescribed muscle relaxant. In recent years, this drug has been increasingly abused. The effects of carisoprodol have been attributed to its metabolite, meprobamate--a controlled substance that produces sedation via GABAA receptors (GABAAR). Given the structural similarities between carisoprodol and meprobamate, we used electrophysiological and behavioral approaches to investigate whether carisoprodol directly affects GABAAR function. In whole-cell patch clamp studies, carisoprodol allosterically modulated and directly activated human alpha1beta2gamma2 GABAAR function in a barbiturate-like manner. At millimolar concentrations, inhibitory effects were apparent. Similar allosteric effects were not observed for homomeric rho1 GABA or glycine alpha1 receptors. In the absence of GABA, carisoprodol produced picrotoxin-sensitive, inward currents that were significantly larger than those produced by meprobamate, suggesting carisoprodol may directly produce GABAergic effects in vivo. When administered to mice via intraperitoneal or oral routes, carisoprodol elicited locomotor depression within 8 to 12 minutes following injection. Intraperitoneal administration of meprobamate depressed locomotor activity in the same time frame. In drug discrimination studies with carisoprodol-trained rats, the GABAergic ligands pentobarbital, chlordiazepoxide, and meprobamate each substituted for carisoprodol in a dose-dependent manner. In accordance with findings in vitro, the discriminative stimulus effects of carisoprodol were antagonized by a barbiturate antagonist, bemegride, but not by the benzodiazepine site antagonist flumazenil. Collectively, the results of our studies in vivo and in vitro suggest the barbiturate-like effects of carisoprodol may not be due solely to its metabolite, meprobamate. Furthermore, the functional traits we have identified likely contribute to the abuse potential of carisoprodol .

Gonzalez, Lorie A., Gatch, Michael B. Taylor, Cynthia M Bell-Horner, Cathy L. Forster, Michael J.Dillon, Glenn H.
Carisoprodol-Mediated Modulation of GABAA Receptors: In Vitro and in Vivo Studies Journal of Pharmacology and Experimental Therapeutics YR 2009 FD May 01 VO 329 IS 2 SP 827 OP 837
DO 10.1124/jpet.109.151142



Full Text

 

[daddysgone]

I have nothing to add beyond my obvious experience that clearly carisoprodol with a unique profile and that it is def. not just a prodrug of meprobamate.

It's anxiolytic effects are blocked by naloxone? That surprises me.

On another note- you are a soon to be medical doctor?
When did this happen? Are you applying to med school?

 

[negrogesic]

Good to hear from you daddysgone, its been a while. I applied and was accepted to a number of schools, mainly bbecause of my high grades, deceptively high MCAT (I am very good at taking standardized test) and my history as a tech then P.A. in veterinary got me in. But I never accepted, waited until recently and talked my way back in by offering to retake the MCAT to prove my high score (once again over 40, a 1 point higher than the first testing-no I am no genius, I am just tricky).

I was able to use my P.A. in veterinary med and glowing D.V.M. recommendations to in effect bypass the first year and a half (yes I had to take further test, I fucked up a bit but still scored high relative to my peers. Beyond that I don't feel comfortable being too specific here, but you (daddysgone) know how to directly contact me (I had your phone #, lost it, you may still have my private line which has not changed, if not, I will provide it for you or others I know personally). I can explain and give you specifics, shortcuts and tricks to getting into a good med school.

While it is financially adverse for me to practice, I may use it philanthropically, especially in addiction medicine and educating these moronic but sincere psychiatrists (the easiest to get through with specialty). Yes it may seem worrisome for a notorious opioid addict and by consequence, a depressant addict (not my DOC) known as "negrogesic", who has been quoted (news to me) in medical texts, such as ("Injecting Illicit Drugs"), where they quote my "negrogesic" vague and inccorrect description about the ease of isolating morphine and its more potent "cousin". Oh and that guy in Hawaii who Dave (the late personal friend but even more troubled fellow OD veteran and polydrug abuser, known as "Phreex") first informed me that someone has tried to impersonate me me (type negrogesic into google)

 

[negrogesic]

Sorry about these fragmented replies I am trying to figure out this new android, which I am trying to use the voice recognition to do the text, not typing.

In regards to the point of the thread, I was hoping a chemist could make some conjectures beyond the vague info available on the compound.....

 

[nuke]

Good to hear from you daddysgone, its been a while. I applied and was accepted to a number of schools, mainly bbecause of my high grades, deceptively high MCAT (I am very good at taking standardized test) and my history as a tech then P.A. in veterinary got me in. But I never accepted, waited until recently and talked my way back in by offering to retake the MCAT to prove my high score (once again over 40, a 1 point higher than the first testing-no I am no genius, I am just tricky).

I was able to use my P.A. in veterinary med and glowing D.V.M. recommendations to in effect bypass the first year and a half (yes I had to take further test, I fucked up a bit but still scored high relative to my peers. Beyond that I don't feel comfortable being too specific here, but you (daddysgone) know how to directly contact me (I had your phone #, lost it, you may still have my private line which has not changed, if not, I will provide it for you or others I know personally). I can explain and give you specifics, shortcuts and tricks to getting into a good med school.

While it is financially adverse for me to practice, I may use it philanthropically, especially in addiction medicine and educating these moronic but sincere psychiatrists (the easiest to get through with specialty). Yes it may seem worrisome for a notorious opioid addict and by consequence, a depressant addict (not my DOC) known as "negrogesic", who has been quoted (news to me) in medical texts, such as ("Injecting Illicit Drugs"), where they quote my "negrogesic" vague and inccorrect description about the ease of isolating morphine and its more potent "cousin". Oh and that guy in Hawaii who Dave (the late personal friend but even more troubled fellow OD veteran and polydrug abuser, known as "Phreex") first informed me that someone has tried to impersonate me me (type negrogesic into google)

A 40T+ is a really good score, you should consider medicine. I'm not sure it's a contraindication to be a drug abuser and practice medicine, I have known a few doctors who did, but with the way malpractice is in the US you would probably do yourself good to find some kind of opioid maintenance therapy so you could practice favourably. You also don't have to make loads of money off of practising if you don't want to -- there are plenty of free clinics that operate without huge benefit to the doctors themselves.

In fact, I would think it would benefit the field to have a doctor with first hand experience in drug addiction...

 

[negrogesic]

^^^^My concern is not about money, I am a successful speculator with a good business education and the associated connections. Furthermore, while my drug of choice are opioids (particularly morphine and the potent thebaine semi-synths, certain morphinans like levorphanol, open phenylheptylamines like M-done/the elusive Ketogan and finally some of the fentanyl's) I don't "need" them.

I would never take a GABAergic drug alone for recreation; I have experienced the horrors from ultra high dose benzo dependency, getting off of methadone, even from 380mg, was a joke in comparison. I would certainly not practice if I felt I could hurt someone, and again, have ZERO financial incentive to practice.

I am not a "terminal opioid addict" so to speak, I can detox and abstain with surprising ease, I don't need opioid's to function nor have any pain so chronic that I need centrally acting analgesic, NMDA-antagonists or related palliatives etc.

I initially underwent this med-school endeavor with mixed motives, namely credibility, but I am by nature compassionate to human suffering and am technically or perhaps comparatively, a rather adept anesthetist.

In any case, please, what is the deal Soma?