A multifaceted GABAA receptor modulator: Functional properties and mechanism of action of the sedative-hypnotic and recreational drug methaqualone (Quaalude)

Harriet Hammer; Benjamin M. Bader; C Ehnert; C Bundgaard; Lennart Bunch; Kirsten Hoestgaard-Jensen; Olaf H-U Schroeder; Jesper F Bastlund; A Gramowski-Voß; Anders A. Jensen

doi:10.1124/mol.115.099291

A multifaceted GABAA receptor modulator: Functional properties and mechanism of action of the sedative-hypnotic and recreational drug methaqualone (Quaalude)

Harriet Hammer, Benjamin M. Bader, C Ehnert, C Bundgaard, Lennart Bunch, Kirsten Hoestgaard-Jensen, Olaf H-U Schroeder, Jesper F Bastlund, A Gramowski-Voß, Anders A. Jensen

27 Citations (Scopus)

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.

Original language	English
Journal	Molecular Pharmacology
Volume	88
Issue number	2
Pages (from-to)	401-420
Number of pages	20
ISSN	0026-895X
DOIs	https://doi.org/10.1124/mol.115.099291
Publication status	Published - 1 Aug 2015

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Hammer, H., Bader, B. M., Ehnert, C., Bundgaard, C., Bunch, L., Hoestgaard-Jensen, K., Schroeder, O. H.-U., Bastlund, J. F., Gramowski-Voß, A., & Jensen, A. A. (2015). A multifaceted GABAA receptor modulator: Functional properties and mechanism of action of the sedative-hypnotic and recreational drug methaqualone (Quaalude). Molecular Pharmacology, 88(2), 401-420. https://doi.org/10.1124/mol.115.099291

A multifaceted GABAA receptor modulator: Functional properties and mechanism of action of the sedative-hypnotic and recreational drug methaqualone (Quaalude). / Hammer, Harriet; Bader, Benjamin M.; Ehnert, C et al.
In: Molecular Pharmacology, Vol. 88, No. 2, 01.08.2015, p. 401-420.

Research output: Contribution to journal › Journal article › Research › peer-review

Hammer, H, Bader, BM, Ehnert, C, Bundgaard, C, Bunch, L, Hoestgaard-Jensen, K, Schroeder, OH-U, Bastlund, JF, Gramowski-Voß, A & Jensen, AA 2015, 'A multifaceted GABAA receptor modulator: Functional properties and mechanism of action of the sedative-hypnotic and recreational drug methaqualone (Quaalude)', Molecular Pharmacology, vol. 88, no. 2, pp. 401-420. https://doi.org/10.1124/mol.115.099291

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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. ",

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AU - Bundgaard, C

AU - Bunch, Lennart

AU - Hoestgaard-Jensen, Kirsten

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AU - Gramowski-Voß, A

AU - Jensen, Anders A.

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N2 - 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.

AB - 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.

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A multifaceted GABAA receptor modulator: Functional properties and mechanism of action of the sedative-hypnotic and recreational drug methaqualone (Quaalude)

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