Insights into functional pharmacology of α 1 GABA A receptors: how much does partial activation at the benzodiazepine site matter?

Rationale Synthesis of ligands inactive or with low activity at α 1 GABA A receptors has become the key concept for development of novel, more tolerable benzodiazepine (BZ)-like drugs. WYS8, a remarkably (105 times) α 1 -subtype selective partial positive modulator, may serve as a pharmacological tool for refining the role of α 1 GABA A receptors in mediation of BZs’ effects. Objectives Here, the effects of WYS8 on GABA-induced currents and on diazepam-induced potentiation of recombinant BZ-sensitive GABA A receptors were studied in more detail. In addition, the behavioral profile of WYS8 (0.2, 1, and 10 mg/kg i.p.), on its own and in combination with diazepam, was tested in the spontaneous locomotor activity, elevated plus maze, grip strength, rotarod, and pentylenetetrazole tests. Results WYS8, applied at an in vivo attainable concentration of 100 nM, reduced the stimulation of GABA currents by 1 μM diazepam by 57 % at α 1 β 3 γ 2 , but not at α 2 β 3 γ 2 , α 3 β 3 γ 2 , or α 5 β 3 γ 2 GABA A receptors. The administration of WYS8 alone induced negligible behavioral consequences. When combined with diazepam, WYS8 caused a reduction in sedation, muscle relaxation, and anticonvulsant activity, as compared with this BZ alone, whereas ataxia was preserved, and the anxiolytic effect of 2 mg/kg diazepam was unmasked. Conclusions Hence, a partial instead of full activation at α 1 GABA A receptors did not necessarily result in the attenuation of the effects assumed to be mediated by activation of these receptors, or in the full preservation of the effects mediated by activation of other GABA A receptors. Thus, the role of α 1 GABA A receptors appears more complex than that proposed by genetic studies.