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| [PMID]: | 26056160 |
| [Au] Autor: | Hammer H; Bader BM; Ehnert C; Bundgaard C; Bunch L; Hoestgaard-Jensen K; Schroeder OH; Bastlund JF; Gramowski-Voß A; Jensen AA |
| [Ad] Endereço: | 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.). |
| [Ti] Título: | A Multifaceted GABAA Receptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude). |
| [So] Source: | Mol Pharmacol;88(2):401-20, 2015 Aug. | | [Is] ISSN: | 1521-0111 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | 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 α1,2,3,5ß2,3γ2S GABAA receptors (GABAARs) expressed in Xenopus oocytes, whereas it displayed highly diverse functionalities at the α4,6ß1,2,3δ GABAAR subtypes, ranging from inactivity (α4ß1δ), through negative (α6ß1δ) or positive allosteric modulation (α4ß2δ, α6ß2,3δ), to superagonism (α4ß3δ). 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 ß((+))/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. |
| [Mh] Termos MeSH primário: |
Encéfalo/efeitos dos fármacos
Hipnóticos e Sedativos/farmacologia
Metaqualona/farmacologia
Receptores de GABA-A/genética
Receptores de GABA-A/metabolismo
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| [Mh] Termos MeSH secundário: |
Animais
Sítios de Ligação
Seres Humanos
Locomoção/efeitos dos fármacos
Masculino
Camundongos
Mutação
Receptores de GABA-A/química
Drogas Ilícitas
Xenopus/genética
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| [Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (Hypnotics and Sedatives); 0 (Receptors, GABA-A); 0 (Street Drugs); 7ZKH8MQW6T (Methaqualone) |
| [Em] Mês de entrada: | 1509 |
| [Cu] Atualização por classe: | 170220 |
[Lr] Data última revisão:
| 170220 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 150610 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1124/mol.115.099291 |
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