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Voltage-clamp evidence of GABAA receptor subunit-specific effects: pharmacodynamic fingerprint of chlornordiazepam, the major active metabolite of mexazolam, as compared to alprazolam, bromazepam, and zolpidem

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Abstract

Background

Anxiolytic benzodiazepines, due to their clinical effectiveness, are one of the most prescribed drugs worldwide, despite being associated with sedative effects and impaired psychomotor and cognitive performance. Not every GABAA receptor functions in the same manner. Those containing α1 subunits are associated with sleep regulation and have a greater effect on the sedative-hypnotic benzodiazepines, whereas those containing α2 and/or α3 subunits are associated with anxiety phenomena and have a greater effect on the anxiolytic benzodiazepines. Therefore, characterization of the selectivity profile of anxiolytic drugs could translate into a significant clinical impact.

Methods

The present study pharmacodynamically evaluated chlornordiazepam, the main active metabolite of mexazolam, upon GABAA receptors containing α2 and/or α3, anxiety-related, and those containing an α1 subunit, associated with sleep modulation.

Results

As shown by whole-cell patch-clamp data, chlornordiazepam potentiated GABA-evoked current amplitude in α2 and α3 containing receptors without changing the current amplitude in α1 containing receptors. However, current decay time increased, particularly in GABAA receptors containing α1 subunits. In contrast, other anxiolytic benzodiazepines such as alprazolam, bromazepam, and zolpidem, all increased currents associated with GABAA receptors containing the α1 subunit.

Conclusions

This novel evidence demonstrates that mexazolam (through its main metabolite chlornordiazepam) has a “pharmacodynamic fingerprint” that correlates better with an anxiolytic profile and fewer sedative effects, when compared to alprazolam, bromazepam and zolpidem, explaining clinical trial outcomes with these drugs. This also highlights the relevance of the pharmacological selectivity over GABAA receptor subtypes in the selection of benzodiazepines, in addition to their clinical performance and pharmacokinetic characteristics.

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Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ALZ:

Alprazolam

BRO:

Bromazepam

CND:

Chlornordiazepam

GABAA :

Gamma-aminobutyric acid A

MEX:

Mexazolam

ZLP:

Zolpidem

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Funding

These electrophysiological experiments were conducted by B’SYS and supported by BIAL.

Author information

Authors and Affiliations

  1. Department of Research and Development, BIAL - Portela & C.ª, S.A., À Av. da Siderurgia Nacional, Coronado (S. Romão E S. Mamede), 4745-457, Trofa, Portugal

    Hélder Fernandes, Vânia Batalha, Maria João Bonifácio & Patrício Soares-da-Silva

  2. Center for Health Technology and Services Research, Department of Community Medicine, Information and Health Decision Sciences, Faculty of Medicine, University of Porto, Porto, Portugal

    Hélder Fernandes

  3. B’SYS GmbH, Witterswil, Switzerland

    Ellen Braksator & Simon Hebeisen

  4. Pharmacology and Therapeutics Unit, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal

    Maria Augusta Vieira-Coelho & Patrício Soares-da-Silva

  5. Psychiatry and Mental Health Clinic, São João University Hospital Centre, Porto, Portugal

    Maria Augusta Vieira-Coelho

  6. MedInUP, Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal

    Patrício Soares-da-Silva

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Contributions

HF, VB, MJB, MAV and PSS: conceptually designed the study, wrote the protocol and the first draft of the manuscript. SH and EB: conducted the laboratory experiments and wrote the study report. All authors contributed to and have approved the final manuscript.

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Correspondence to Hélder Fernandes.

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Conflict of interest

Hélder Fernandes, Vânia Batalha, Maria João Bonifácio and Patrício Soares-da-Silva were employees of BIAL—Portela & Cª S.A at the time of the study. Simon Hebeisen and Ellen Braksator were employees of B'SYS GmbH at the time of the study. B'SYS GmbH received a grant from BIAL—Portela & Cª, S.A.

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Fernandes, H., Batalha, V., Braksator, E. et al. Voltage-clamp evidence of GABAA receptor subunit-specific effects: pharmacodynamic fingerprint of chlornordiazepam, the major active metabolite of mexazolam, as compared to alprazolam, bromazepam, and zolpidem. Pharmacol. Rep 74, 956–968 (2022). https://doi.org/10.1007/s43440-022-00411-x

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