Ethanol binding to receptors profile

[serotonin2A]

if gaba-a is the only target for alcohol addiction, then all those stupid benzos i tried would work, but they dont. anyway, you probably know better than me

I was specifically referring to the withdrawal syndrome --the intoxication is multifaceted. Did benzos fail to suppress your withdrawal symptoms?

 

[asecin]

i was talking about general well being on alcohol not comparable to benzos. they helped with anxiety, seizure threshold and aggravation but not long term solution to feeling even slightly "ok" without alcohol. so they just come as very quick solution to first 1-2 days of alcohol withdrawal, they have zero merit long term abstinence and that is what im trying to figure out, how many more things to consider to get the full benefit of abstinence. that is, how many more receptors, what else is there to inhibit and influence beyond GABAs

 

[Nagelfar]

And, in fact, the argument made in your post (that ethanol and Ro15-4315 are structurally dissimilar) would seem to imply that they are unlikely to have any specific interactions.

Plenty of analogs are not structurally similar, and to that I agree and if that's the specific of my post then we can agree on as much. If however, the ethyl group is what reacts in Ro15 and ethanol, then something about the molecular weight interaction is the same ultimately from ethanol, despite the large difference in molecular weight and bulk; it's an interesting thing to bring up either way.

 

[serotonin2A]

Plenty of analogs are not structurally similar, and to that I agree and if that's the specific of my post then we can agree on as much. If however, the ethyl group is what reacts in Ro15 and ethanol, then something about the molecular weight interaction is the same ultimately from ethanol, despite the large difference in molecular weight and bulk; it's an interesting thing to bring up either way.

You should definitely read the study I cited. It is not the ethyl group in Ro15 that is important but rather the azido group. Their rationale is that flumazenil (which is Ro15 minus the azido group) and Ro15 bind to the same site, but only Ro15 can interact with ethanol. What they are proposing is that flumazenil and ethanol bind to immediately adjacent but distinct sites, but that the azido group in Ro15 kind of sticks out into the alcohol site.

 

[Cotcha Yankinov]

if gaba-a is the only target for alcohol addiction, then all those stupid benzos i tried would work, but they dont. anyway, you probably know better than me

I know altered subunit composition of benzodiazepine receptors can play a role in benzo tolerance (meaning that if you were a previous user of benzos, altered benzo receptors could have played a role in your non-response), as well as upregulation of downstream excitatory Glutamate, which if it is seen with alcohol like it is with benzo use then I suppose that could play a role. I suppose barbiturates would have been more interesting to try (although dangerous) and then for the Glutamate, perhaps Perampanel for glutamate blockade?

I'd be curious if ibogaine would help as well. I forget if studies found if it helped with alcohol abuse by animals. But if it helps with withdrawal/sobriety for opiate addicts then maybe it could help with alcohol withdrawal/sobriety.

 

[Limpet_Chicken]

IIRC alcohol (EtOH) agonizes GABAa primarily, AMPARs and KARs at extremely (near OD) levels, plus induces a switch from inhibitory MOR activity to excitatory, presumably fucking with G-protein coupling but that last is a total guess.

I do know that it causes glutamatergic hyperactivity plus opioidergic nastiness of some description, alcohol withdrawal at least sensitizes (murine model) animals to the effects of opioid WD, and makes the WD worse.


I'd suggest barbiturates for the alcohol addiction, or a combination of very low dose chlormethiazole (barb site ligand , no glutamatergic action, pure clean barb-site agonist) plus an intermediate acting strong barb like amobarbital or better still, pentobarb, because barbiturates are both GABAa agonists that can direcly open the chloride channel of GABAaRs in the absence of GABA, and also they are AMPAr antagonists, that undergo a type of ligand-trapping within the AMPAr receptor 'clamshell' region, that leaves the barbs stuck there, and leaving the bound AMPARs in a closed, agonist-bound, ligand trapped state.

Adding memantine would be a good idea to leave NMDA activity as it should be relatively alone, ignoring the feedforward impulse propagation from AMPAr stimulation, and addition of perampanel, telampanel, tezampamel etc would unlikely be a bad idea.

 

[Cotcha Yankinov]

Considering alcohol does have those effects on endogenous opoid metabolism, maybe a bit of ultra low dose naltrexone could prove useful like it does for opiate withdrawal and tolerance. Just to be clear, that's talking around .1mg from studies I've seen.

 

[JacksinPA]

I apologize if the following information has already been posted.

Years ago I called on Hoffman-LaRoche in Nutley, NJ, but I learned over lunch at Glaxo HQ at the time in Research Triangle Park from a former Roche development chemist about Ro15-4315 . He told me that they could get lab rats totally anesthisized with alcohol, then give them this benzo. In no time they were active & alert. With the number of drunk people who wind up in ERs, you would think that this drug (described as an inverse agonist) would be a great help to emergency medicine doctors trying to work on accident victims. But a combination of ethical concerns & the likeliehood of diversion into the party drug scene made them kill it.

 

[clubcard]

The subjective positive effects are mediated by the α5 diazepam sensitive sites. Some of the negatives are α1 mediated (look how crazy the Z drugs can act on people) but most is mediated by it's NMDA activity. Certainly the ataxia, confabulation and aggression are.

This isn't a guess. I KNOW people on here tested peyezolam.

 

[JacksinPA]

More from the Wikipedia article on this drug:

Unfortunately Ro15-4513 had several disadvantages that made it unsuitable for development and marketing. Its fairly short half-life means that several repeated doses would have to be given over an extended period, since if only one dose were used it would wear off before the alcohol had been metabolised and the patient would relapse (similar to the problems with renarcotization seen when treating overdoses of long-acting opioids such as methadone with short-acting antagonists such as naloxone). Also because of its GABA antagonist effects, Ro15-4513 causes serious side-effects including both anxiety, and at higher doses, convulsions, which would require careful control of dosing and would cause complications in clinical use. Another problem is that alcohol's effects are not purely mediated by GABA receptors; at higher doses alcohol binds to several other targets as well, so while Ro15-4513 is an effective antidote against moderate levels of alcohol intoxication, it might be ineffective at treating life-threatening overdoses.

Also, Roche was concerned about the legal implications of introducing an alcohol antidote, as Ro15-4513 blocks the effects of ethanol but does not remove it from the bloodstream, which could lead to potential problems, as the effects of the alcohol would be masked only temporarily. As a result, patients might, for instance, feel that they are sober and discharge themselves from hospital once the drug took effect, then become drunk again once it wore off, possibly crashing their car or having other accidents that might lead to legal consequences for Roche.

 

[Cotcha Yankinov]

The ethics of having this available as an agent to help one sober up before driving home from the bar et cetera could be complex. I believe some college students were using amphetamines in that manner.

 

[JacksinPA]

The stated side effects, such as anxiety, are likely hard to handle if you're hoping to avoid a police blue light special on you way home from a kegger. And convulsions, too. Hoping to manage correct & repeated dosing while inebriated doesn't sound like a good idea to me.