Benzos The GABA(A) Receptor Complex and Benzodiazepines

[kokaino]

We all know that benzos work by increasing the efficiency of a natural brain chemical, GABA, to decrease the excitability of neurons. This reduces the communication between neurons and therefore has a calming effect on many of the functions of the brain.

The GABA(A) receptor complex has many different subunits, which in turn have isoforms or otherwise known as subtypes (α1-6, β1-4, γ1-3, δ, ε, θ, and ρ1-2). Different benzodiazepines (BZD) have different affinities for GABA(A) receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity. Only three of the subunits (α, β, and γ) are benzodiazepine sensitive. The α (alpha) subunit has 6 subtypes, but only α1, α2, α3, and α5 are BZD sensitive. The β (beta) subunit has 4 subtypes, but only the β3 subtype is BZD sensitive. The γ (gamma) subunit has 3 subtypes, but only the γ2 subtype is BZD sensitive.

Subunits from only one class (α) or two classes (α and β) can form functional GABA receptors under experimental conditions, but subunits from three classes (α, β, and γ) are needed for full receptor function. These three subunits also compose most of the GABA(A) receptors in the mammalian brain.


The Alpha (α) subunit

The most important subunit is the "alpha" (α) and its subtypes isoforms (α1,2,3,and 5). The alpha subunit is responsible for mediating most of the effects of the benzos. All benzos bind to this subunit but they also all have different affinitie levels to the different subtypes.

α1 subtype: Sedation, respiratory depression, sleep, ataxia, motor-impairment, amnesia, anti-convulsive, and reinforcing behavior.

α2 subtype: Anxiolysis, disinhibition

α3 subtype: Anxiolysis, anti-convulsive, muscle relaxation

α5 subtype: Learning and memory, amnesia, minor sedation

α3 & α5 subtype: Sensorimotor information processing

The Beta (β) and Gamma (γ) subunits

γ2 subtype: Physical dependence, respiratory depression

β3 subtype: Anti-convulsive, minor sedation, muscle relaxation, various other reactions related to respiration. This receptor subtype is a barbiturate receptor.

Benzos affinity to the GABA(A) receptors

High α1 affinity: midazolam, triazolam, flunitrazepam, temazepam, lormetazepam, nitrazepam, brotizolam, nimetazepam, loprazolam, and flutoprazepam.

Low to Moderate α1 affinity: wide range of 1,4 benzodiazepines including diazepam, estazolam, flurazepam, oxazepam, lorazepam, alprazolam, bromazepam, camazepam, quazepam (highly selective affinity), clonazepam, medazepam, nordazepam, chlordiazepoxide (very weak affinity), clorazepate, and most other benzo as all benzos are α1 agonists with varying degrees of affinity levels. Also included here are the nonbenzodiazepine "z-drugs" such as zolpidem, zaleplon, zopiclone, and eszopiclone which are all highly selective of the α1 subtype receptor but with only weak to moderate affinity.

High α2 affinity: diazepam, clonazepam, bromazepam, lorazepam, alprazolam, camazepam, nitrazepam, loprazolam, lormetazepam, and flutoprazepam.

Moderate α2 affinity: oxazepam, prazepam, phenazepam, temazepam, flunitrazepam, halazepam, midazolam, and other less commonly known benzos.

Weak α2 affinity: triazolam, chlordiazepoxide (stronger affinity for α3), brotizolam, quazepam, tetrazepam (stronger affinity for α3), and a few others.

High α3 affinity: diazepam, clonazepam, temazepam, lorazepam, tetrazepam, flunitrazepam, nimetazepam, phenazepam, and bromazepam.

Moderate α3 affinity: alprazolam, adinazolam, estazolam, chlordiazepoxide, clorazepate, and flurazepam.

High γ2 affinity (these benzos are the most physically addictive): temazepam, brotizolam, triazolam, alprazolam, lorazepam, loprazolam, midazolam, flunitrazepam, clonazepam, lormetazepam, flutoprazepam, nitrazepam, nimetazepam, and estazolam

Low to moderate γ2 affinity: diazepam, chlordiazepoxide, oxazepam, and most other benzos.

High β3 affinity: mostly the hypnotics (nitrazepam, temazepam, triazolam, etc)

Low to moderate β3 affinity: diazepam, alprazolam, most other benzos.


Source of all this info is this book which I purchased. It has A LOT of more useful info. It's worth its price.

 

[Captain.Heroin]

Awesome, thank you! I am adding this to the OD Directory.

 

[Kenny7822]

Awesome thread, thank you.

 

[NeighborhoodThreat]

^^Seconded, this is really awesome information! Thanks CH for adding to the directory!

 

[Starshowers]

Thank you for this. Excellent.

 

[Nagelfar]

What in the benzo class has "the highest" affinity for γ2?

Also are there any specific ligands for γ2?

 

[AlphaMethylPhenyl]

This is off-topic but can someone please tell me why I never see anything about an a4 receptor?

Edit: I'd probably look into buying the book if it didn't just center around GABA. Thanks though.

 

[xxxyyy]

nice work, man, thanks. really informative.

 

[walterdini]

I agree w/ everyone in applauding you work, but I'f I may make a suggestion:

Add a table of contens at the beginig, or a glossary/index at the end.

Whenever I find great informv posts like this, they are often so visually challanging I ignore them

 

[phatass]

interesting !

 

[golden1]

from this can anyone speculate why even large doses of clonazolam are much worse at stopping trips, getting rid of headaches, and at the same time gives less of that destructive brain frying feeling while tapering, compared to etizolam and others?
clonazolam has much higher antianxiety effects and sedation, yet it seems it doesn't "comfort" a certain subtype that calms certain brain activity down nearly as much as etizolam. Etizolam would remove any negative feeling in my head(headache, overexcitaton-wise) but clonazolam doesn't unless you take a much higher dose. Yet clonazolam certainly feels like it should.. given every other aspect surpassses etizolam

 

[Lorne???]

This is a great post, however some of the information seems questionable... at clinical doses, Temazepam is not a very effective anti-convulsive, in comparison to Lorazepam, and especially Clonazepam;

So a high affinity for A3 seems unlikely; could nitpick, though 90% it seems plausible, and is a good post, again.

Plan on making an updated and accurate (preferably thourough) Benzodiazepine chart, and have found a great calculator, which is fairly accurate in conversions, and provides Tmax, T1/2(updated figures) and even lipid solubility and dosage forms.

Want to provide accurate info, and dispel some misconceptions; also, making a chart that takes acute vs. chronic would be an improvement itself.

Any help appreciated

 

[Scrofula]

Make sure it's clear that (as far as I know) there aren't any selective benzos available--at clinical doses, they all bind all sites to some extent, and at higher doses, it becomes clinically irrelevant.

IOW, be careful suggesting one benzo is more or less sedating than another, because at recreational levels, they'll all be sedating. Most people using this site aren't looking for the best benzo to control their epilepsy.

A lot of info here is dusty, so updates are welcome. Please include references.

 

[Lorne???]

Yes, want to post some info first and then post references.

Some things are common knowledge; diazepam(Valium) is highly lipophyllic, so it has a rapid onset even PO, yet it quickly exits CNS as is then redistributed extensively, which is why it wears off so fast;

A single dose of Lorazepam lasts longer than a single dose of Valium, as Ativan is the opposite (delayed onset, extended duration) and clonazepam is similar, except very high binding affinity and slow elimination lend it a longer duration;

Hadapaper w/ binding affinities, though it is lost.

Check out the benzo thread, already started, doubt it would’ve disputed, at least it is a start

 

[Oxynormal]

Very clearly explained, thanks.

 

[markosheehan]

Are all marketed benzodiazepines full agonists at these sites?

Does anyone have binding info on clobazam in terms of the subunits.?

Has anyone been testing the new selective partial agonists out there like imidazenil and pagaclone and TPA023b Etc

 

[Scrofula]

Benzos aren't technically agonists, so "full" or "partial" doesn't really apply.

But the benzos on the market do show "preference" for different subunit isoforms, and some isoforms are more or less associated with effects like sedation. But they will all bind to all isoforms at some concentration, making the distinctions not tremendously helpful, IMO.

 

[Lorne???]

... ^ Sorry though it’s well known that Nordazepam is a partial agonist, and antagonist’s also exist.

What is your basis?

And benzodiazepines can have markedly different effects, so binding profile is worth a study, at least medically, though agree that any potent benzo will have most of the classical effects, although some clonazepam have effects at serotonin, and some are more hypnotic at equivalent doses

 

[Scrofula]

OK, this is as good a thread to go into it as any. Keep in mind that some references get sloppy with the terminology. Because this is BL, in the Other Drugs forum, I think it's actually relevant to be pedantic with it, because some folks on this site use bona fide GABA agonists (hello amanita eaters!).

An agonist technically binds to the same site as an endogenous ligand (GABA in this case) and elicits the same or very similar response.
An antagonist binds to same site but doesn't do anything--although it might prevent the native ligand or other drugs from binding, or binding as often.
(An inverse agonist binds to the same site but causes an opposite reaction--you need a receptor with some constitutive activity for this, I don't think GABAaR counts.)

Then you have allosteric modulators, which can be positive or negative (or neutral). There is a separate site on the receptor where these bind; on their own they (the positive ones) don't activate it, they simply affect the way GABA binds.

Benzos have a specific site (the BZD-site) they prefer, barbiturates have a whole different site. One allows GABA to initiate higher-frequency openings, the other for longer duration. Because they are two separate sites, with two different activities, they are synergistic and very dangerous together.

There are other drugs that do bind at the GABA-binding pocket, like muscimol and gaboxidol, and there are antagonists that also bind there. There are drugs that simply plug up the channel. There's also the benzo antidote that you could arguably call an antagonist, but all it does it bind to the BZD site without altering it, and prevent other benzos from binding.

There are different isoforms of the GABAaR alpha subunit, and different benzos have different affinities for them. The different isoforms are associated with slightly different effects, probably less due to the isoform, and more because they're expressed in different parts of the brain and body.

Here's the thing: Benzo A might have a 50nM Km for alpha1 (more sleepy), and 5nM for alpha3 (more anxiolytic). You could say that benzo A is less sleepy and better for anxiety. But if benzo A is percolating through your brain at 100nM, there's more than enough of it to also bind alpha1 and knock you out. Now, there are like six different alpha isoforms, but it's pretty debatable how much different character they really have in your brain--of the two dozen or so total variants, most look like they're expressed outside the synapse, and many are actually involved in development.

So really, we're looking for "selective" benzos that have affinities with more like 100x or 1000x differences between isoforms (to target different brain regions). A helpful statistic would be the ratio of affinities, where available.

I'm not challenging the worthiness of putting it all in a table, in fact I'm a big fan of tables and charts. My caveat, from the HR perspective, is in over-selling the differences between benzos as though they are fine wines. Like wine, you can maybe appreciate the difference with the first glass, but after that you'll get just as drunk on a bottle of Barefoot Blush.

Time to onset and half-lives of active metabolites is probably the most helpful.

And as long as you're making the effort, properly classifying them biochemically as positive allosteric modulators of the GABAa receptor.

 

[Slow_Mobius]

This is a great post, however some of the information seems questionable... at clinical doses, Temazepam is not a very effective anti-convulsive, in comparison to Lorazepam, and especially Clonazepam;

So a high affinity for A3 seems unlikely; could nitpick, though 90% it seems plausible, and is a good post, again.

Plan on making an updated and accurate (preferably thourough) Benzodiazepine chart, and have found a great calculator, which is fairly accurate in conversions, and provides Tmax, T1/2(updated figures) and even lipid solubility and dosage forms.

Want to provide accurate info, and dispel some misconceptions; also, making a chart that takes acute vs. chronic would be an improvement itself.

Any help appreciated

I think it's a great idea. Have you tried looking for any review articles that have compiled a lot of binding affinity data? I'm not sure if anyone has done something like that, but it's probably worth a look.

One concern I have is that different experimental conditions can yield very different affinities. That's might make it difficult or even impossible to accurately compare binding data across the board. But organizing the biochemical data would be a great start IMO