GABA receptors and Sedative/Hypnotics ("Sleep Meds")

While there seem to be several different types of prescription sleep aids, all (or at least the vast majority) seem to work be targeting certain GABA receptors.

Benzodiazepines seem to be the least selective, and therefore have an affinity for many GABA receptors. Newer drugs (Ambien, Sonata) seem to have a more targeted effect.

From RxList.com:

In contrast to the benzodiazepines, which non-selectively bind to and activate all three omega receptor subtypes, zolpidem in vitro binds the (w1) receptor preferentially. The(w1) receptor is found primarily on the Lamina IV of the sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. This selective binding of zolpidem on the (w1) receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses.

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The newest drug to be approved is Lunesta (eszopiclone). I believe the the actual mechanism of action is technically unknown, its sedative/hypnotic properties are most likely a result of its interaction with certain GABA receptors.

I'm just wondering if anyone knows the exact mechanism of action of eszopiclone...I believe it's just an isomer of IMOVANE (zopiclone), but I don't know anything about zopiclone either. Any other information or comparision/contrast of any or all of the sedative/hypnotics would be greatly appreciated.

Edit: I received an Email Notification that this thread had received a reply, so I clicked the link, but there are no replies! Anyone know how that could happen? The only thing I can think of is that someone replied then decided to delete their response.

I've been waiting for this new drug launch for a long time now, as I have been dealing with chronic insomnia for the past few years and don't like the idea of using Zolpidem for more than for a few days at a time.

The exact mechanism of action of eszopiclone as a hypnotic is unknown, but its effect is believed to be as a result of its interaction with GABA-receptor complexes at binding domains located close to or allosterically coupled to benzo receptors. Eszopiclone is a nonbenzodiazepine hypnotic that is a pyrrolopyrazine derivative of the cyclopyrrolone class with a structure unrelated to pyralopyrimidines, imidazopyridines, benzos, barbiturates or other drugs with known hypnotic properties.

With eszopiclone we are indeed setting sail into uncharted waters. It's an exciting little molecule, which I imagine may very well prove useful beyond the treatment of insomnia, but with all newly approved pharmacological entities let's cross our fingers and hope that we don't end up learning that it increases the risk of stroke or causes an early onset of parkinsons in the next few years.

SG

Well Sebastians_ghost, it's not technically all that new.

From http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=105&STORY=/www/story/09-06-2000/0001305295

(S)-Zopiclone is a single-isomer version of racemic zopiclone, a non-benzodiazepine, rapid-acting
hypnotic prescribed worldwide for the treatment of insomnia.
Racemic zopiclone is marketed by Rhone Poulenc-Rorer in approximately 80 countries worldwide under the brand names of IMOVANE(R) and AMOBAN(R), and has never been submitted for approval in the United States. In 1999, racemic zopiclone was the leading treatment for sleep disorders outside the United States.

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And http://www.ascp.com/public/pubs/tcp/1997/apr/newdrugs.html shows that zopiclone was listed as a "Potential New Drug for 1997 and Beyond."

For some reason, I had difficulty finding when zopiclone was actually released. This may be due to the fact that (IIRC) it was never approved for use in the US. Any way, Lunesta (eszopiclone) is just the single isome of IMOVANE (racemic zopicloen), which has been around for at least several years.

When you say exact mechanism, what do you mean? I could find its affinity for various GABA-A complexes, but that wouldn't really explain it, would it? Likewise, as far as I can remember, it increases GABA-A currents, but not really channel inactivation, but that doesn't explain much either.

Hehe, this topic is right up my alley, because my lab studies the molecular pharmacology of GABA receptors.

I don't know what's up with rxlist talking about the "omega" subunit of the GABA(A) receptor. Maybe they mean the alpha1 subunit?

The GABA(A) receptor is a pentameric chloride channel. The benzodiazepine binding site is located at the interface between a gamma2 subunit and an alpha subunit of subtype alpha1, alpha2, alpha3, or alpha5. Benzodiazepines act allosterically at this site, causing more current to flow through the channel and thereby increasing inhibition of the postsynaptic cell. Evidence from genetic, pharmacological, physiological, and behavioral studies indicates that GABA(A) alpha1 subunit-containing receptors mediate the sedative effects of benzodiazepines. Other studies have shown that alpha2- and alpha3-containing GABA(A) receptors are likely to mediate the anxiolytic effects, and that the effects of benzos on memory involve alpha5-containing receptors. Zolpidem (and also eszopiclone) is an alpha1-selective nonbenzodiazepine agonist of the benzodiazepine receptor. Its unique pharmacological profile may primarily be due to this property, though differences in how it modulates the channel can not be excluded.

Omega is another word for BZ... Omega 1,2 = BZ1,2...

a bit off topic, whats the mechanism behind GABA side effects such as heart rate and breathing changes and the facial tingling?

Breathing is simple; breathing is controlled by a group of neurons which steadily depolarize until they fire, repolarize, and begin to depolarize again: they have so called "pace maker" activity. Increasing GABAergic activity with a benzo, decreases the rate of depolarization, leading to slower cell firing, and slower breathing.

The heart rate thing I'm not so sure about, but I geuss it's to do with general decreased sympathetic tone.

The tingling you were referring to, is that when you're having an attack?
If so, it's due to hyperventilation. For me it usually starts in my fingertips/facial area...

BilZ0r- but you said oral and even IV GABA supplements don't cross the BBB!
are those neurons that control breathing and heart rate not in the brain?

^^^GABA supplements do not, because they are fairly polar. However, benzodiazepines are quite nonpolar and they enter the brain freely. The group of neurons that controls respiration is in the brainstem, at the base of the brain.

What are all the GABA receptors? I'm under the impression that it's the GABA A receptor that is responsible for the sedative effects of benzodiazepines and the other receptors are responsible for anxiolytic/anti-panic, anticonvulsant, myorelaxant properties. Newer sleep drugs, like Ambien, are more selective and I believe only target the GABA A receptor. Now if this is the case, why hasn't someone made a benzo. or other type of drug that targets all but the GABA A receptors? It seems like this what provide all the benefits of a benzo without the often annoying sedative properties (unless you're using it as a sedative/hypnotic/sleep aid)? So, what's the deal? Why no non-sedating benzo? I don't understand why they couldn't do this if they can make such drugs as Ambien that are selective, why couldn't they make a drug that was selective so that it different have an affect on the GABA A receptor?

EDIT: It appears as if I'm wrong about what GABA receptors are responsible for the various effects (anxiolytic, myorelaxant, anticonvulsant) but if you ignore my mistakes, why can't a drug be made to target all BUT the GABA receptor responsible for sedation (whichever one(s) that may be)?

All of the effects you mention are coverned by the GABA-A receptor complex. But not all GABA-A receptors are the same. There are all kinds of subunits that make up the GABA-A receptor, and so different drugs can have different affinities for different GABA-A receptor complex. If a particular kind of GABA-A receptor complex is expressed in some area, and not in the rest of the brain, then a drug which is selective for that particular subunit make up can be selective for a particular effect...

Yeah, BilZ0r, I messed that up...I found out that there were GABA-A subunits or subreceptors AFTER posting (which I tried to explain when I editted the post). I was under the (wrong) impression that the various effects of benzos were caused by different receptors (i.e. GABA-A, GABA-B, etc.) and didn't realize (until after posting) that the various effects of benzos were caused by various subunits/subreceptors of the GABA-A complex.

Now that we have that clarified, let me modify my question. I'm under the impression that Ambien affects one (or only a few, or at least fewer than benzos) GABA-A subreceptor - the one(s) (mainly) responsible for the sedative properties. On the other hand, I'm under the impression that benzos (in general) affect many, if not all, of the GABA-A subreceptors...of course some might have a stronger affinity for certain subreceptors (hence various uses, sedative/hypnotic, anxiolytic, myorelaxant, anticonvulsant) but they all (I think) have at least some of those properties.

So, why couldn't a drug (either a benzo or whole different class of drug) be made that targets all the GABA-A receptors that are not responsible for the sedative properties? Some like the opposite of Ambien, in the sense that it targets every GABA-A subreceptor that Ambien does not affect? If this could be done, I think it would be great...a drug that could be used as an anxiolytic, myorelaxant, and anticonvulsant with few (or no) sedative properties (a major drawback of benzos, especially when taken during the day for generalized anxiety or a daytime panic attack). Obviously if it were a benzo (or probably even if it were a whole different class of drug) it would still have the tolerance/dependence/addiction problem, but it would be better in the sense that it isn't a sedative at all (or just a tiny bit).

Well "sedative" is a very broad term. They do have benzos which are generally exclusively hypnotic (zolpidem, Zaleplon) and not generally anxiolytic, or euphoric...

The problem lies in, as I said, that a particular kind of GABA-A receptor complex needs to be expressed in a particular area of the brain, and that area needs to be responsible for the particular function. Then it's just up to medicinal chemists to find a selective ligand.

If on the the other hand, the area in question has many kinds of GABA-A receptor complexes, and those complexes are expressed in other parts of the brain, then a selective drug can not be made.

A general sedative action is probably going to happen from potentiation of GABA function in any area of the frontal cortex, which expresses most of the common GABA-A complexes, so I find it unlikely.

Heres some tables that come out of an article still in press, written by one of my Colleagues, soon to be published in Progress in Neurobiology

I just feel the overpowering urge to compliment all of you on this fantastically detailed information (bilZor in particular, that chart really helped me make sense of the preceding conversations).

As my involvement with Ambien, and now Xanax, grew, so too did my interest in the GABA complexes and what exactly mediates their effects.

Anyway, carry on, but fuck what a fantastic forum - dont let this one go.

Peace,
Vaya:D

[VERY USEFUL AND INFORMATIVE STATEMENTS REMOVED BY A STUPID PARANOID MODERATOR]

Thanks again 5-HT2

5-HT2, if you did have "VERY USEFUL AND INFORMATIVE STATEMENTS" in your last post, could you please re-post them in a way such that it will not be offensive or make anyone feel "paranoid?" BilZ0r, not trying to question your judgement, just hoping that 5-HT2 could provide the information WITHOUT the portions you found offensive (or you could provide the information you removed w/o the offensive portions)...thanks.

Of interest to the general public, he said that the alpha3 subunit is expressed in the reticular nucleus of the thalamus and is associated with seizure pathophysiology as well as the fact that the delta subunit is effected by ethanol at pharmacologically relavent concentrations

Thanks BilZ0r. Now, which subunits are in any way responsible for anxiolytic effects (preferably in order from most pronounced anxiolytic effects to least)? Also, if you could list the other effects of these subunits (mainly sedative, but also myorelaxant, anticonvulsant...) along with the relative "strength" of their other effects, that'd be great. I'm trying to figure out which GABA-A subunits a drug could target to provide the greatest anxiolytic effect with the least drowsiness. I'm guessing some degree of drowsiness is unavoidable when "playing around with" the GABA system. I just don't see why this hasn't been explored...is my logic flawed somewhere or could this just be a potentially wonderful drug that no one's "discovered" yet?

From the looks of BilZ0r's chart, only 4 subunits have been identified as being responsible for some type of anxiolytic effects (and only one of those is identified as having sedative effects as well). I'll list them again so you don't have to refer back to the chart:
Alpha 2: Behavioural sensitivity to cocaine, and anxiolytic actions of benzodiazepines
Alpha 4: Are involved in sezures, electroconvulsive therapy, pre-menstrual syndrome, stress, and ethanol dependence
Gamma 2: Involved in seizures, anxiety, righting reflex, abnormal gait, andpost-synaptic clustering
Delta: Mediates the sedative, anxiolytic, and pro-absence effects of neurosteroids
Binding sites within he adult brain (%) are as follows 4-28, 0-15, 50-94, and 0-23 respectively. I'm not exactly sure what this means though. What would have if a drug selectively targeted only the 4 subunits I mentioned (maybe with the greatest effect on the gamma 2 subunit due to the high % of binding sites and least effect on delta subunit due to the potential sedative side effects)? Would this be the "holy grail of anti-anxiety medication" that I'm looking for?

So, let's try to put together a list of drugs that could do what I've describe. I'm interested to know if there are already drugs that existed that are highly selective for some of the GABA-A receptor subunits, especially the 4 mentioned (alpha 2 and 4, gamma 2, and delta).

Feel free to "think outside the box" or "expand your paradigms" and don't just limit the quest for a great anti-anxiety drug to effects on the GABA systems. If you feel there are any other mechanisms of actions that could prove helpful in combatting anxiety, feel free to mention a drug (or possible drug) that uses that mechanism. I should specify, I'm looking for a drug that could be used not as a "cure" (kind of like how A/Ds are supposedly to prevent/reduce anxiety/panic attacks) but rather something more like benzos (that temporarily mask/eliminate the symptom of anxiety, whether it be a quick acting drug for panic or longer acting one for generalized anxiety)...I know, another long post with lots of not so wonderfully organized thoughts (damn dope) so feel free to ask me to clarify anything...I know I've probably said it 5 times, but I'm REALLY interested in finding a potential drug better than anything on the market at reducing anxiety while having less sedating effects than any benzo on the market (think of something more potent in terms of anxiolytic effects than Xanax, Ativan, or Rohypnol, but significantly less sedating than any benzo).

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