title: 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 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 central nervous system (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 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 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.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (H.H., L.B., K.H.-J., A.A.J.); NeuroProof, Rostock, Germany (B.M.B., C.E., O.H.-U.S., A.G.-V.); and H. Lundbeck A/S, Valby, Denmark (C.B., J.F.B.).
authors.forename: Harriet
authors.initials: H
authors.lastname: Hammer
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (H.H., L.B., K.H.-J., A.A.J.); NeuroProof, Rostock, Germany (B.M.B., C.E., O.H.-U.S., A.G.-V.); and H. Lundbeck A/S, Valby, Denmark (C.B., J.F.B.).
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Bader
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (H.H., L.B., K.H.-J., A.A.J.); NeuroProof, Rostock, Germany (B.M.B., C.E., O.H.-U.S., A.G.-V.); and H. Lundbeck A/S, Valby, Denmark (C.B., J.F.B.).
authors.forename: Corina
authors.initials: C
authors.lastname: Ehnert
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (H.H., L.B., K.H.-J., A.A.J.); NeuroProof, Rostock, Germany (B.M.B., C.E., O.H.-U.S., A.G.-V.); and H. Lundbeck A/S, Valby, Denmark (C.B., J.F.B.).
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (H.H., L.B., K.H.-J., A.A.J.); NeuroProof, Rostock, Germany (B.M.B., C.E., O.H.-U.S., A.G.-V.); and H. Lundbeck A/S, Valby, Denmark (C.B., J.F.B.).
authors.forename: Lennart
authors.initials: L
authors.lastname: Bunch
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (H.H., L.B., K.H.-J., A.A.J.); NeuroProof, Rostock, Germany (B.M.B., C.E., O.H.-U.S., A.G.-V.); and H. Lundbeck A/S, Valby, Denmark (C.B., J.F.B.).
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hoestgaard-Jensen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (H.H., L.B., K.H.-J., A.A.J.); NeuroProof, Rostock, Germany (B.M.B., C.E., O.H.-U.S., A.G.-V.); and H. Lundbeck A/S, Valby, Denmark (C.B., J.F.B.).
authors.forename: Olaf H-U
authors.initials: OH
authors.lastname: Schroeder
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (H.H., L.B., K.H.-J., A.A.J.); NeuroProof, Rostock, Germany (B.M.B., C.E., O.H.-U.S., A.G.-V.); and H. Lundbeck A/S, Valby, Denmark (C.B., J.F.B.).
authors.forename: Jesper F
authors.initials: JF
authors.lastname: Bastlund
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (H.H., L.B., K.H.-J., A.A.J.); NeuroProof, Rostock, Germany (B.M.B., C.E., O.H.-U.S., A.G.-V.); and H. Lundbeck A/S, Valby, Denmark (C.B., J.F.B.).
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gramowski-Voß
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (H.H., L.B., K.H.-J., A.A.J.); NeuroProof, Rostock, Germany (B.M.B., C.E., O.H.-U.S., A.G.-V.); and H. Lundbeck A/S, Valby, Denmark (C.B., J.F.B.) aaj@sund.ku.dk.
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D013287:Illicit Drugs; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008702:Methaqualone / Q000494:pharmacology*; D051379:Mice; D009154:Mutation; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014981:Xenopus / Q000235:genetics
chemical_list: D006993:Hypnotics and Sedatives; D013287:Illicit Drugs; D011963:Receptors, GABA-A; D008702:Methaqualone