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Methaqualone's mechanism of action

jspun

jspun

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Does know or can anyone speculate about methaqualone's mechanism of action. There are aspects of MQs pharmacology that are unique compared to other drugs in the class. I would think there might be inhibition of AMPA and stimulation of GABA A analogous to the barbituates. Might there be a novel site (other than the barbituate receptor) that MQ binds to on the GABA ionophore complex? Might there be an endorphinergic component?(methaqualone has antitussive properties). How about catecholamines? What might be the mechanism by which MQ causes convulsions in overdose?
 
weird I was sure I posted in this thread already...

Primary recreational effects are almost certainly GABA-Aergic in nature, without a lot of added effects.

Convulsions are almost certainly due to AMPA effects.

antitussive effects due to opioid effects? Doubtful. there are lots of drugs that have antitussive effects without mu or sigma effects.
 
The exact mechanism was not studied and is, therefore, not published. There was some talk about this topic here at Bluelight, see for example my post in this thread.

Using the search engine will certainly reveal more info.

Peace! Murphy
 
I seem to recall that it was blocked by a GABA A antagonist (antagonist where I forget), though.
 
Convulsions are almost certainly due to AMPA effects.
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I would have thought that AMPA inhibition would raise the seizure threashold. Could an excitotoxic metabolite result in overdose seizure activity?

The exact mechanism was not studied and is, therefore, not published. There was some talk about this topic here at Bluelight, see for example my post in this thread.
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Read through thread. Interesting stuff about competative binding study and MOA mediated atleast in part through BZP receptor. I think the possibility exists that methaqualone might effect GABA-A neurotransmission through a novel target. Its dose response curve seems to be more barbituate like. Thanks guys for responses!
 
Hmm... You're right, it is an AMPA antagonist. I don't have a good explanation then.

One thing I do know, is that MMQ is far worse in this respect. It's possible that the small modification turns it into an AMPA agonist. The difference between agonists and antagonists are often quite small, but predictable within a class. I don't think this class has been studied enough.
 
From link provided by MC:

[Where benzodiazepines potentiate the effect that GABA binding has, barbiturates do the same, in a way, but by increasing the length of time the chloride channel is open./QUOTE]

My GABA/ barbituate pharmacology is rusty. Goodman and Gilman mention that benzos increase the freqency of channel opening but barbs the length of time it stays open. The net effect of both is enlarging GABA induced chloride curreents. Both enhance the binding of GABA to its receptor.

MC posted some good stuff:

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:
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Ro 17-1788. Isn't that picrotoxin? Not sure of its mechansim of action but I believe its pharmacological effects are opposite of that of barbituates on Cl- channels. Was the cocnlusion that MMQ doesn't bind to a site on the alpha/beta subunit because its effects aren't antagonized by Ro-17-1788?


I worked in a neuropharmacology lab several years ago. The PI who is a heavy in DA and reinforcement believed that MMQ had the same functionality as barbs and thus binds to the same site on the GABA ionophore complex. This is a ligand gated channel but the BZD receptor is allosteric to the channel protein on the gamma subunit. Sites for barbs, steroid anaethetics, and EtOH have been found on the channel protein (alpha/beta subunits). I believe there might be a unique site on the GABA-A ligand gated channel. If i'm not mistaken in vitro binding studies tell you about competative binding but not whether a substance is a agonist, antagonist, patial agaonist, ext... at the receptor. In this case a functionality study is needed to determine this. Maybe MMQ serves as an antagonist or partial agaonist or agonist/antagonist at the receptor. Maybe its just an antagonist and does nothing but block diazepams effect. Maybe it doesn't stabalize the GABA molecule with its receptor( increasing affinity of receptor for ligand) but stimulates GABA neurotransmission in another way. It would be interesting if there is a methaqualone site that awaits discovery and a mystery putative ligand out there for that receptor.

Its possible that seizures in overdose are caused by a toxic metabolite that accumulates in overdose or maybe antagonizes GABA. Also there are anecdotal reports of the drug being energizing, euphoric, and increasing libido and intensity of orgasm in a manner unique compared other sedatives. Exagerated DA release that lowers the seizure threshold significantly in oversdose. Mechanism for DA release AMPA antagonism?

Interesting fact, Barbs and possibly MMQ are thought to antagonize AMPA. EtOH NMDA. Maybe differences negligible? Looking at my old neurochemistry notes and it would appear that AMPA and NMDA revceptor occur simutaneously on post synaptic glutamenergic fibers so the net effect of antagonizing one would be equivalent to antagonizing the other because same fibers are effected.

Opiate component. Why not. Strong evidence for EtOH causing reinforcement impart through endorphinergic system. Many people describe the high as being heroin like for MMQ. Antitussive properties aside, I believe MMQ might potentiate analgesia atleast when used in combination with other narcs. Atleast it doesn't produce the hyperalgesia produced by barbituates.

Anyway this is an interesting drug and I hope that one day research on this drug resumes. Hope this makes sense- tired, might have to modify post tommorow.
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The RO-17-1788 is flumazenil which is widely used in medicine as a benzo antagonist. Now this makes more sense
 
Hammilton said:
I seem to recall that it was blocked by a GABA A antagonist (antagonist where I forget), though.
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jspun said:
MC posted some good stuff:
Further support for a benzodiazepine-competitive binding mode was established, using Ro 15-1788 as GABA-receptor probe:
Click to expand...
Click to expand...
Okay, Ro 15-1788 is Flumazenil.
@Hammilton: Is this also the GABA A antagonist that you recall?

@jspun: Could you give a reference for the claim (although it is not yours), because I think this stuff is still exciting..
 
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