Abstract
In the present study we have elucidated the functional characteristics and mechanism of action of methaqualone (2-methyl-3-o-tolyl-4(3H)-quinazolinone, Quaalude®), an infamous sedative-hypnotic and recreational drug from the 1960-70s. Methaqualone was demonstrated to be a positive allosteric modulator (PAM) at human α1,2,3,5β2,3γ2S GABAA receptors (GABAARs) expressed in Xenopus oocytes, whereas it displayed highly diverse functionalities at the α4,6β1,2,3δ GABAAR subtypes, ranging from inactivity (α4β1δ), through negative (α6β1δ) or positive allosteric modulation (α4β2δ, α6β2,3δ), to superagonism (α4β3δ). Methaqualone did not interact with the benzodiazepine, barbiturate or neurosteroid binding sites in the GABAAR. Instead, the compound is proposed to act through the transmembrane β(+)/α(-) subunit interface of the receptor, possibly targeting a site overlapping with that of the general anesthetic etomidate. The negligible activities displayed by methaqualone at numerous neurotransmitter receptors and transporters in an elaborate screening for additional putative CNS targets suggest that it is a selective GABAAR modulator. The mode of action of methaqualone was further investigated in multichannel recordings from primary frontal cortex networks, where the overall activity changes induced by the compound at 1-100 μM concentrations were very similar to those mediated by other CNS depressants. Finally, the free methaqualone concentrations in mouse brain arising from doses producing significant in vivo effects in assays for locomotion and anticonvulsant activity were found to correlate fairly well with its potencies as a modulator at the recombinant GABAARs. Hence, we propose that the multifaceted functional properties exhibited by methaqualone at GABAARs give rise to its effects as a therapeutic and recreational drug.
- The American Society for Pharmacology and Experimental Therapeutics