A Multifaceted GABAA Receptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

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 1960s-1970s. Methaqualone was demonstrated to be a positive allosteric modulator at human a 1,2,3,5 b 2,3 g 2S GABA A receptors (GABA A Rs) expressed in Xenopus oocytes, whereas it displayed highly diverse functionalities at the a 4,6 b 1,2,3 d GABA A R subtypes, ranging from inactivity (Methaqualone did not interact with the benzodiazepine, barbiturate, or neurosteroid binding sites in the GABA A R. Instead, the compound is proposed to act through the transmembrane b(1) /a (-) 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 central nervous system (CNS) targets suggest that it is a selective GABA A R 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 mM concentrations were quite similar to those mediated by other CNS depressants. Finally, the free methaqualone concentrations in the mouse brain arising from doses producing significant in vivo effects in assays for locomotion and anticonvulsant activity correlated fairly well with its potencies as a modulator at the recombinant GABA A Rs. Hence, we propose that the multifaceted functional properties exhibited by methaqualone at GABA A Rs give rise to its effects as a therapeutic and recreational drug.

International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans

“…Methaqualone exhibited negligible activities at numerous neurotransmitter receptors and transporters, suggesting that it is a selective GABA A receptor modulator. In addition, the doses producing significant in vivo effects in assays for locomotion and anticonvulsant activity correlated fairly well with its potencies as a modulator of recombinant GABA A receptors (Hammer et al, 2015).…”

“…Unfortunately, most of these full concentration-response curves were not published. through negative (a6b1d) or positive allosteric modulation (a4b2d, a6b2,3d) to extremely strong effects at a4b3d (Hammer et al, 2015). Methaqualone was proposed to interact with the transmembrane b+a2 interface, possibly targeting a site overlapping with that of the general anesthetic etomidate.…”

Functional characterization of GABAA receptor-mediated modulation of cortical neuron network activity in microelectrode array recordings

“…In average 25 active units (from 32 electrodes) were recorded per network, with peaks of up to 100 units per network. The data from the recordings with DS2 (alone) has been published previously [ 22 ], whereas the other data presented in this study has not.…”

“…The use of microelectrode arrays (MEAs) enables the recordings of extracellular action potentials of cultured neurons and thus elucidatation of the activity characteristics of neuronal networks. For more than 20 years, this technological platform has been used for studying neurotoxic effects of compounds and toxins [ 15 – 17 ] but also in studies investigating the functional modes of action of ligands [ 17 – 22 ]. In the present study, we have applied this technology to study the effects induced by a broad selection of pharmacological tools characterized by different GABA A R subtype-selectivity profiles at the spontaneous activity patterns of primary neuronal networks from murine frontal cortex, and in this way we have elucidated GABA A R-mediated effects on neuronal activity in a more holistic manner than possible by conventional slice and patch-clamp electrophysiology.…”

Evodiamine Reduces Caffeine-Induced Sleep Disturbances and Excitation in Mice

“…GABA A receptors have several subunits, including the α (1–6), β (1–4), γ (1–3), δ (1), ε (1) subunits ( Seifi et al ., 2014 ). The common pentameric GABA A receptor is composed of two α subunits, two β subunits, and either a γ or δ subunit ( Hammer et al ., 2015 ). Each GABA A receptor subunit plays a distinct role depending on the brain region, with the hypothalamus exhibiting its own pattern of functionality ( Wafford and Ebert, 2006 ).…”