Benzodiazepines vs. Qualones.

[LabRatNW]

There's an eerie similarity in their basic structures. anyone know if their MOAs are similar?

6-7-6 centered vs 6-6-6 centered rings. (Quaaludes just now became creepy for a whole new reason...)

 

[flacky]

From an abstract: "At low, nonsedative doses the drug produces anticonvulsant effects, and at higher doses, muscle-relaxant and sedative effects. It appears that the mechanism(s) of action of methaqualone is on GABA deficiency or receptor blockade, rather than on glycine receptors."

I wouldn't say that their structures are amazingly similar, though.

 

[negrogesic]

Benzos are positive allosteric modulators of GABA-A, whereas methaqualone acts directly on GABA-A. Also, unlike benzos, methaqualone causes a direct gating of the GABA-A chloride ion channel, thus leading to an increased toxicity/overdose risk when compared to benzos...

 

[Hammilton]

Benzos are positive allosteric modulators of GABA-A, whereas methaqualone acts directly on GABA-A. Also, unlike benzos, methaqualone causes a direct gating of the GABA-A chloride ion channel, thus leading to an increased toxicity/overdose risk when compared to benzos...

Ah what? Virtually all abused depressants, excepting muscimol and maybe someday gaboxadol, are positive allosteric modulators.

There's a big protein which is the GABA-A receptor, and there's the GABA site, and then there are all sorts of allosteric sites. I do not believe that methaqualone binds to any of the benzodiazepine receptors (which are, actually, allosteric sites on the GABA-A receptor complex), but there are many other allosteric sites which BZDs don't bind to.

I feel like I am largely to blame for this misunderstanding. 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.

I hope I have this correct.

 

[negrogesic]

Yes, i never argued that, but my characterization of methaqualones "direct" action was a little off.

Of course, both act by potentiating GABA, but methaqualone directly increases the duration of channel opening (or more appropriately, it increases longest opening state while decreasing shortest opening), whereas benzos work by increasing the overall number of times the channel is opened. The BZD receptor is coupled to barb binding sites, but I am not sure if methaqualone binds only to barb binding sites or BZD sites as well.

 

[MurphyClox]

Benzos are positive allosteric modulators of GABA-A, whereas methaqualone acts directly on GABA-A. Also, unlike benzos, methaqualone causes a direct gating of the GABA-A chloride ion channel, thus leading to an increased toxicity/overdose risk when compared to benzos...

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:

Methaqualone (Mtq; quaaludes or 'ludes) is a controlled substance, having a molecular structure related to the imidiazobenzodiazepine series of drugs, that has gained some notoriety recently due to its history of widespread abuse on the street. Users report experiencing peripheral paresthesia and transient numbness on body parts receiving dense cutaneous innervation (lips, fingertips, etc.). Since the receptive-field (RF)-sizes of many primary somatosensory (S1) cortical neurones are controlled by local, gamma-aminobutyric acid (GABA)-mediated inhibitory processes, we tested Mtq to see whether its clinical symptoms might have a basis in an action through central GABA-mediated synaptic processes. This report supports this contention and describes a likely pharmacological mechanism involved as one being related to the Ro 15-1788-sensitive benzodiazepine (Bzd) recognition site(s) of the GABA receptor complex.

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

 

[MurphyClox]

An extension to my last post:

In Naunyn-Schmiedeberg Arch Pharm 1978, 305, p.23, W.E. Müller et al were able to show for MMQ an IC50 of 150 µM against [3H]diazepam-labeled GABA-receptors. Notably, the authors used brain homogenates (male Sprague-Dawley rat brains without medulla-pons), as it was ususal practice in these times.
I can imagine that the actual IC50 would be lower if there were specific GABA-receptor subtypes studied, because the failed binding to certain (i.e. not active) subtypes tampers the results...

- Murphy

 

[Hammilton]

In Naunyn-Schmiedeberg Arch Pharm 1978, 305, p.23, W.E. Müller et al were able to show for MMQ an IC50 of 150 µM against [3H]diazepam-labeled GABA-receptors. Notably, the authors used brain homogenates (male Sprague-Dawley rat brains without medulla-pons), as it was ususal practice in these times.
I can imagine that the actual IC50 would be lower if there were specific GABA-receptor subtypes studied, because the failed binding to certain (i.e. not active) subtypes tampers the results...

Yeah, unfortunately methaqualone research has pretty much stopped, and our knowledge of it hasn't benefitted from technology advances.

150um seems to be awfully high, even with 300mg for an active dose, I would imagine it to be substantially more potent. IIRC, there were carbamates with IC50s in the 150um range and those had doses measured by grams.

 

[negrogesic]

Murply, please keep in mind that I remarked the following:

my characterization of methaqualones "direct" action was a little off.

My overall assumption was that methaqualone behaves more like barbs than benzos...

 

[MurphyClox]

[1]Murply, please keep in mind that I remarked the following:

my characterization of methaqualones "direct" action was a little off.

[2]My overall assumption was that methaqualone behaves more like barbs than benzos...

[1] Oki doki!
[2] Based on personal experience or the literature data?

- Murphy

 

[negrogesic]

Based on my personal experience, methaqualone has more in common with pentobarbital than diazepam...

Like pentobarb, methaqualone was flat out euphoric (unlike the rather obscure benzo euphoria), and the sedation was similarly heavy-handed. Also quite like barbs, methaqualone can cause a hangover, though not as bad...