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

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 GABA(A) receptor functions in the same manner. Those containing alpha 1 subunits are associated with sleep regulation and have a greater effect on the sedative-hypnotic benzodiazepines, whereas those containing alpha 2 and/or alpha 3 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 GABA(A) receptors containing alpha 2 and/or alpha 3, anxiety-related, and those containing an alpha 1 subunit, associated with sleep modulation. Results As shown by whole-cell patch-clamp data, chlornordiazepam potentiated GABA-evoked current amplitude in alpha 2 and alpha 3 containing receptors without changing the current amplitude in alpha 1 containing receptors. However, current decay time increased, particularly in GABA(A) receptors containing alpha 1 subunits. In contrast, other anxiolytic benzodiazepines such as alprazolam, bromazepam, and zolpidem, all increased currents associated with GABA(A) receptors containing the alpha 1 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 GABA(A) receptor subtypes in the selection of benzodiazepines, in addition to their clinical performance and pharmacokinetic characteristics.

Automated summary

The selectivity of anxiolytic drugs for different types of GABA(A) receptors is crucial and can explain the results of clinical trials. This study demonstrates that the main metabolite of mexazolam, chlornordiazepam, has better anxiolytic properties and fewer sedative effects compared to other anxiolytic benzodiazepines like alprazolam, bromazepam, and zolpidem, which have a greater effect on receptors containing the alpha 1 subunit.