Ethanol binding to receptors profile

[Renald]

Anybody has it, at least its binding affinity to main targets as GABA and NMDA? https://www.bindingdb.org has binding profiles only for drugs, and alcohol is not considered a drug.

 

[serotonin2A]

Alcohol often doesn't bind to specific site(s) that have been clearly defined and hence specific affinity values cannot be calculated. It is an allosteric modulator of different ion channels and the potencies of such effects have been reported, but that is not the same as the binding affinity. This has nothing to do with the fact that alcohol may or may not be a drug (it is).

 

[Renald]

Alcohol doesn't bind to specific site(s) and hence specific affinity values cannot be calculated. It is an allosteric modulator of different ion channels and the potencies of such effects have been reported, but that is not the same as the binding affinity. This has nothing to do with the fact that alcohol may or may not be a drug (it is).

So we cant calculate its NMDA and GABA binding affinity? Benzos are also allosteric modulators of GABAa, but their affinity is known.

 

[serotonin2A]

So we cant calculate its NMDA and GABA binding affinity? Benzos are also allosteric modulators of GABAa, but their affinity is known.

Benzodiazepines interact with a specific binding site that is part of the GABA-A channel, usually with at least moderate affinity. By contrast, it isn't clear whether there is actually a specific binding site for ethanol. Part of the problem is that binding studies require use of a radioligand that has high affinity and low levels of nonspecific binding (ie, most of the binding should be to the site of interest). Alcohol however tends to stick to membranes. Since alcohols and similar compounds are the only thing known to bind to that potential "site", there isn't any useful way to label the site, so no way to measure affinity.

I should note that there is a benzodiazepine derivative known as Ro15–4513 that was suspected to bind to the same site as ethanol on a subset of GABA-A receptors. But it is far from clear that they compete for the same site and such an interaction wouldn't allow you to define the affinity of ethanol for most GABA-A channels, let alone its other targets.

 

[Renald]

Ok, and what about NMDA receptor binding of ethanol? It also cant be evaluated?

 

[serotonin2A]

Ok, and what about NMDA receptor binding of ethanol? It also cant be evaluated?

Everything I wrote is applicable to all the channels where alcohol acts.

 

[asecin]

so when are scientists going to figure out how alcohol works on the brain. its the oldest drug been used and abused by people and modern science still cannot figure out what it does to the brain exactly. amazing!

 

[d1nach]

It gets your brain f***'d up lol thats why I dont like drinking I feel like smashed rather than like a clean specific feeling

 

[serotonin2A]

so when are scientists going to figure out how alcohol works on the brain. its the oldest drug been used and abused by people and modern science still cannot figure out what it does to the brain exactly. amazing!

Scientists actually have a pretty clear understanding about how alcohol works in the brain (allosteric modulator of GABA-A, NMDA, AMPA, 5-HT3, and nACh receptors, plus some downstream effects on dopamine and endogenous opioids). What isn't known is the affinity of alcohol for the receptors it binds to, but that information is not required to understand how alcohol works.

 

[Nagelfar]

I think alcohol, being so simple a chemical structure, stays along membranes and interfers with ion channels to function allosterically to modulate many channels that are otherwise mediated by larger compounds by receptor sites, which alcohol is too small to hit specifically, but can broadly interfere with as a broad spectrum of ionic change.

This is (ethyl/drinking) alcohol (ethanol):

I should note that there is a benzodiazepine derivative known as Ro15–4513 that was suspected to bind to the same site as ethanol on a subset of GABA-A receptors. But it is far from clear that they compete for the same site and such an interaction wouldn't allow you to define the affinity of ethanol for most GABA-A channels, let alone its other targets.

Just 'cause Ro15-4513 is an inverse agonist of sites (possibly upstream) of what alcohol changes to counteract alcohol; doesn't mean alcohol binds to its same site, necessarily.

^(this isn't directed at you sero, but to the point of the OP's question) that is Ro15-4513, which inversely/counteracts a lot of alcohols sedative effects. Now do you see a correlation in structure? Of course not, alcohol is too simple.

 

[serotonin2A]

I think alcohol, being so simple a chemical structure, stays along membranes and interfers with ion channels to function allosterically to modulate many channels that are otherwise mediated by larger compounds by receptor sites, which alcohol is too small to hit specifically, but can broadly interfere with as a broad spectrum of ionic change.

This is (ethyl/drinking) alcohol (ethanol):

Just 'cause Ro15-4513 is an inverse agonist of sites (possibly upstream) of what alcohol changes to counteract alcohol; doesn't mean alcohol binds to its same site, necessarily.

^(this isn't directed at you sero, but to the point of the OP's question) that is Ro15-4513, which inversely/counteracts a lot of alcohols sedative effects. Now do you see a correlation in structure? Of course not, alcohol is too simple.

I wouldn't have written what I did if there wasn't specific evidence that there is a competitive interaction. Yes, the structures of alcohol and Ro15-4513 are completely different, but that doesn't mean that they can't interact with the same site. Someone went through the trouble of tritiating Ro15-4513 and in binding studies there was evidence of competitive displacement of its binding to GABA-A receptors by alcohol.

http://m.pnas.org/content/103/22/8546.full

 

[mike.vick]

I would suspect that there is some GLUTAMATE and GABAb binding, possibly also involvement in Voltage-gated-calcium-channels. And i think it has been confirmed that alcohol has a slight DRI-action right?
Alcohol has the ability to destroy cellular membranes so I wonder if that causes any neurochemicals to be released.

 

[Limpet_Chicken]

That azido moiety looks fuckugly, would make it an irreversible, covalently binding ligand most likely. Nasty as. I wouldn't touch that with a ten foot shit covered pole.



IIRC, EtOH also binds kainate and AMPA receptors but only at very high (near over-)dose levels.

 

[Nagelfar]

I wouldn't have written what I did if there wasn't specific evidence that there is a competitive interaction. Yes, the structures of alcohol and Ro15-4513 are completely different, but that doesn't mean that they can't interact with the same site. Someone went through the trouble of tritiating Ro15-4513 and in binding studies there was evidence of competitive displacement of its binding to GABA-A receptors by alcohol.

http://m.pnas.org/content/103/22/8546.full

Wasn't saying there isn't; as mentioned; I said that wasn't directed at you & I meant that it wasn't ;-) I am speaking of the broad spectrum of effects; regardless of whether a 'master switch' of a ligand is had for alcohol or not. Which was the concept I was trying to convey to the OP

 

[serotonin2A]

Wasn't saying there isn't; as mentioned; I said that wasn't directed at you & I meant that it wasn't ;-) I am speaking of the broad spectrum of effects; regardless of whether a 'master switch' of a ligand is had for alcohol or not. Which was the concept I was trying to convey to the OP

I understand it wasn't directed at me, but the abstract concept you are trying to convey (that alcohol may act nonspecifically) conflicts with the evidence that I posted. 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.

 

[mike.vick]

I understand it wasn't directed at me, but the abstract concept you are trying to convey (that alcohol may act nonspecifically) conflicts with the evidence that I posted. 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.

I thought everyone knew that alcohol doesn't act specifically, it is a very "dirty" drug.

 

[serotonin2A]

I thought everyone knew that alcohol doesn't act specifically, it is a very "dirty" drug.

Some of the actions of ethanol are likely nonspecific, but there is evidence that the effects of ethanol on many receptors are mediated by specific sites. Take a look at the following references:

http://m.pnas.org/content/103/22/8546.full

http://pubs.acs.org/doi/full/10.1021/acschemneuro.5b00246

http://www.ncbi.nlm.nih.gov/pubmed/21676006

http://link.springer.com/article/10.1007/PL00000689

http://onlinelibrary.wiley.com/doi/10.1110/ps.062237606/abstract

At on time, cannabinoids and many anesthetics were though to act non-specifically but are now known to bind to specific sites. Many of ethanol's effects are similar.

 

[asecin]

so to threat alcohol withdrawal and abstinence one should take pills that work on all GABA-A, NMDA, AMPA, 5-HT3, and nACh, serotonin, dopamine and norepinephrine too? thats a lot of pills to do what alcohol does in simplicity

 

[serotonin2A]

so to threat alcohol withdrawal and abstinence one should take pills that work on all GABA-A, NMDA, AMPA, 5-HT3, and nACh, serotonin, dopamine and norepinephrine too? thats a lot of pills to do what alcohol does in simplicity

GABA-A is probably the alcohol target that is the primary mediator of the abstinence syndrome -- hence why benzodiazepines will suppress many of the symptoms. Some of the other targets may not be all that relevant to withdrawal or may mediate side-effects. For example, 5-HT3 probably mediates alcohol-induced nausea.

 

[asecin]

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