How do GABAnergics differ in their mechanism of action.

[vortex30]

GHB, Benzodiazepines, Alcohol and Barbiturates all affect GABA receptors and how GABA is used, or concentrated or whatever. But what exactly are the differences between them? People mix Alcohol with Benzos, its not the safest thing to do, but with moderation on both it can be done with relative safety. But you should never mix GHB with benzos I hear. And with Alcohol its quite risky but seems to be OK in moderate doses like benzos + Alcohol. What's the reason for this?

I don't know much about Barbiturates, but if someone could explain those also it would be nice.

 

[Nibiru]

Different activity at different receptor subtypes. Some chemicals will have more of an affinity towards GABAa or GABAb (or both) receptor subtypes. With GHB, there are actually GHB-specific receptors that GHB binds to in addition to GABA receptors.

 

[Nibiru]

Also, some chemicals of this class have more potential to depress breathing, which is why alcohol and benzos, or alcohol and GHB, or other combinations of CNS depressants can be dangerous. It's also why some, like GHB have such a high potential for dangerous overdosage. Benzos on their own tend to be a lot less acutely toxic than many other sedatives.

And I can't say I know very much about barbiturates at all. Sorry.

 

[slaugh]

what u mean by GABAnergics??????barbiturates,noothrops,what?

 

[dread]

The main difference between benzos and barbiturates is that benzos bind to the benzo site and barbs to the barb site on the GABA-a receptor complex.

Benzos (and other things that bind to the benzo site) are safer because they merely modulate the configuration of the receptor so it has a higher affinity for endogenous GABA. Thus if you overdose on benzos your brain can still downregulate the release of GABA to prevent you from dying.

On barbiturates and others that bind to the barb site, it's different because they don't need the endogenous GABA to activate the receptor. Thus if you overdose on them you're shit out of luck...

GHB on the other hand binds more to GABA b than a, also binds to GHB receptor. I'm not sure if it's a direct agonist or an allosteric modulator like benzos.


For the record, I have mixed GHB with benzos, but this was when I had high tolerance for benzos and I don't recommend it to anyone without a tolerance to gabaergics.

 

[Nibiru]

I don't know how to do the little subscripts and Greek symbols, but what dread is referring by benzo receptor is a very benzodiazepine specific GABAa receptor subtype. If you do a google search or something I'm, sure you could find some good info outlining the GABA system, and different receptor types and subtypes and their ligands.

 

[Hammilton]

The main difference between benzos and barbiturates is that benzos bind to the benzo site and barbs to the barb site on the GABA-a receptor complex.

Benzos (and other things that bind to the benzo site) are safer because they merely modulate the configuration of the receptor so it has a higher affinity for endogenous GABA. Thus if you overdose on benzos your brain can still downregulate the release of GABA to prevent you from dying.

On barbiturates and others that bind to the barb site, it's different because they don't need the endogenous GABA to activate the receptor. Thus if you overdose on them you're shit out of luck...

GHB on the other hand binds more to GABA b than a, also binds to GHB receptor. I'm not sure if it's a direct agonist or an allosteric modulator like benzos.


For the record, I have mixed GHB with benzos, but this was when I had high tolerance for benzos and I don't recommend it to anyone without a tolerance to gabaergics.

The difference between the two is simple. Barb site 'agonists' increase the time the channel is open. Benzo site agonists increase the frequency of channel opening.

additionally, barbs block glutamate, the main excitory neurotransmitter. Block the excitory transmitter, enhance the main inhibitory neurotransmitter, get death.

The fact that barbs open the channel on their own isn't such a big deal- muscimol and gaboxadol do the same things, but they don't cause death.



Both increase the affinity GABA's affinity, that's the basic understanding for all allosteric site agonists, but this is much more complicated.

 

[cegli]

Also, there's a bunch of different subtype receptors for GABAa (and I assume for GABAb as well, though I'm not sure). There's at least a1-a5. a1 seems to be responsible for tiredness and amnesia. benzos are often mostly a1 and a5, sometimes the rest too. Alcohol has action as a4, because there's a benzo antagonist at a4 that reverses the effects of low dose alcohol. This is one of the reasons different benzos feel different.

 

[Hammilton]

You don't really understand what you're saying cegli. They're not "subtypes" of the GABA-A receptor, they're subunits.

the GABA-A receptor is part of the Cys-Loop LGIC family. It's composed of 5 subunits, generally an alpha, a beta and a gamma. GABA-C receptors have a few different types, but they're benzodiazepine insensitive, so not all that important.

GABA-B receptors are GPCRs, and totally unrelated except that they bind GABA. This is why there's no (or very, very little) overlap in GABA-A and GABA-B ligands.

So a GABA-A receptor has 5 subunits arranged, generally, in a pentagonal structure. Binding sites for ligands are located between subunits. Benzos bind in a pocket located between alpha and gamma2 subunits, excepting alpha 4 and 5. Or is it 5 and 6? These are the neurosteroid sensitive subunits.

There are a couple gamma subunits, but IIRC, gamma 2 is the primary one, and the one with which benzos have the highest affinity.

The GABA-A receptor is really really complicated, I think more complicated than most GPCRs, but I'm sure someone will debate me on this point

 

[Nibiru]

You don't really understand what you're saying cegli. They're not "subtypes" of the GABA-A receptor, they're subunits.

the GABA-A receptor is part of the Cys-Loop LGIC family. It's composed of 5 subunits, generally an alpha, a beta and a gamma. GABA-C receptors have a few different types, but they're benzodiazepine insensitive, so not all that important.

GABA-B receptors are GPCRs, and totally unrelated except that they bind GABA. This is why there's no (or very, very little) overlap in GABA-A and GABA-B ligands.

So a GABA-A receptor has 5 subunits arranged, generally, in a pentagonal structure. Binding sites for ligands are located between subunits. Benzos bind in a pocket located between alpha and gamma2 subunits, excepting alpha 4 and 5. Or is it 5 and 6? These are the neurosteroid sensitive subunits.

There are a couple gamma subunits, but IIRC, gamma 2 is the primary one, and the one with which benzos have the highest affinity.

The GABA-A receptor is really really complicated, I think more complicated than most GPCRs, but I'm sure someone will debate me on this point

Feck. I meant to say sub-units not sub-types in the post a little ways above. Sorry.

 

[MurphyClox]

Yo Hammilton, do you know to which subunit(s) methaqualon binds to? Benzo-, barbiturate-, glutamate-, neurosteroid- or any other site??? Is this even known/published?

- Murphy

 

[Hammilton]

I don't know about anything about interaction with glutamate receptors, but it is known to have interaction with GABA/BZD complex, as it produces cross tolerance to diazepam.

I don't know if it was published.

 

[Nagelfar]

...Barb site 'agonists' increase the time the channel is open. Benzo site agonists increase the frequency of channel opening....
...
additionally, barbs block glutamate, the main excitory neurotransmitter. Block the excitory transmitter, enhance the main inhibitory neurotransmitter, get death.
...

Interesting.. on your first paragraph, which would alcohol/ethanol fall under; an agonist of channel staying open or the amount of time it opens? .... This makes me understand why Barbs are a more extreme GABAergic. I'm assuming ethanol is the latter like Benzo's, being less extreme, or they may just have much less affinity?

 

[Hammilton]

Yeah, ethanol is more similar to benzos, but it's a lot more complicated than just GABA interactions.

with barbs though, the anti glutamate thing is key, too.

 

[seep]

I don't know about anything about interaction with glutamate receptors, but it is known to have interaction with GABA/BZD complex, as it produces cross tolerance to diazepam.

I don't know if it was published.

I know that 30 years ago, methaqualone was shown to inhibit the binding of tritiated diazepam (IC50 value of 0.15 mM).

If quaalude is active at the BDZ site, then can there be a substituted quinazolone which retains the anxiolytic and anticonvulsant effects of methaqualone but has minimal sedative/hypnotic effects?

 

[MurphyClox]

Oh wait guys, here is a post of mine who sheds some light on the discussion. I just copied it:

Would you be so kind and provide a reference for the red-marked statements, plz? I'm not aware of any conclusive binding data for methaqualone (with respect to GABA-receptor subtypes resp. the detailed mechanism of action), but would be quite happy if there are any publications that I just missed.

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

My own findings in the literature, in short:
It was published that methaqualone (MMQ), as well as mecloqualone (i.e. MMQ with the tolyl-group replaced by an ortho-chloro-phenyl) were able to inhibit [3H]diazepam binding in vitro (ref [1]). In the same assay, GABA-binding to the receptors was not effected. It must be stressed that the authors did not make a difference between certain GABA-receptor subtypes.

Surprisingly, piriqualone (i.e. MMQ with the 2-methyl replaced by a pyridin-2-yl-vinyl-residue) enhanced [3H]diazepam-binding. Kinetic analysis pointed towards a competitive binding mode for MMQ, with respect to diazepam.

These findings were supported shortly after by cross-tolerance studies, were MMQ was shown to exhibit cross-tolerance for diazepam, but with lesser extend for pentobarbital, barbital and ethanol (ref [2]).

Further support for a benzodiazepine-competitive binding mode was established, using Ro 15-1788 as GABA-receptor probe:


Abstract of ref [3]
See also ref [4] for a structure of Ro 15-1788; the article is available free of charge.


Summary: Except for references without specification of action on certain GABA-receptor subtypes, there is no evidence on the detailed binding mode of MMQ, at least not to my knowledge. Neither are there any publications that discuss the mechanistic mode of action in further detail than the already mentioned ones.
The one thing that we know with relative certainty is that MMQ presumably binds to the same, or partially the same site as benzodiazepines. That's it.

If you know more, please share your data with me.

Regards, Murphy


References:
[1] Drug Dev Res 1986, 7, p.255
[2] Japan J Pharmacol 1988, 46, p.403
[3] Can J Neurol Sci 1990, 17(1), p.30
[4] Br J Clin Pharmacol 1982, 14(5), p.677

 

[Hammilton]

I doubt that a subunit selective analogue of methaqualone could be made, at least not an alpha2 selective ligand.

 

[seep]

Attempts have been made, though from what I gather, nobody altogether understands quinazolones' sedative/hypnotic or anticonvulsant mechanisms. There's a variant that's a selective serotonin antagonist, but I can't remember its name. Also some sort of antihypertensive.

 

[Hammilton]

Not really. I can't find any methaqualone derivatives designed to have subtype selective effects.

Also, you'll find lots of sedative hypnotics / anxiolytics have antihypertensive effects.

 

[madsci]

GABA (gamma hydroxybutyric acid)
Has
an alpha, a beta and a gamma subunit they are all in the same protein complex.
Alcohol and benzodiazapines target teh alpha subunit causing an increase in frequency of channel openings
Barbituates (ketamines) bind the beta subunit increasing the duration of channel opnenings