CONICET | Buscador de Institutos y Recursos Humanos

Compounds targeting the benzodiazepine binding site of the GABAA-R are widely prescribed for the treatment of anxiety disorders, epilepsy, and insomnia as well as for pre-anesthetic sedation and muscle relaxation. It has beenhypothesized that these various pharmacological effects are mediated by differentGABAA-R subtypes. If this hypothesis is correct, then it may be possible todevelop compounds targeting particular GABAA-R subtypes as, for example,selective anxiolytics with a diminished side effect profile. Thepyrazolo[1,5-a]-pyrimidine ocinaplon is anxioselective in both preclinicalstudies and in patients with generalized anxiety disorder, but does not exhibitthe selectivity between alpha1/alpha2-containing receptors for an anxioselective that is predicted by studies using transgenic mice. We hypothesized that thepharmacological properties of ocinaplon in vivo might be influenced by an active biotransformation product with greater selectivity for the alpha2 subunitrelative to alpha1. One hour after administration of ocinaplon, the plasmaconcentration of its primary biotransformation product, DOV 315,090, is 38% ofthe parent compound. The pharmacological properties of DOV 315,090 were assessed using radioligand binding studies and two-electrode voltage clampelectrophysiology. We report that DOV 315,090 possesses modulatory activity atGABAA-Rs, but that its selectivity profile is similar to that of ocinaplon. This implies that DOV 315,090 could contribute to the action of ocinaplon in vivo, butthat the anxioselective properties of ocinaplon cannot be readily explained by a subtype selective effect/action of DOV 315,090. Further inquiry is required toidentify the extent to which different subtypes are involved in the anxiolyticand other pharmacological effects of GABAA-R modulators.Compounds targeting the benzodiazepine binding site of the GABAA-R are widely prescribed for the treatment of anxiety disorders, epilepsy, and insomnia as well as for pre-anesthetic sedation and muscle relaxation. It has beenhypothesized that these various pharmacological effects are mediated by differentGABAA-R subtypes. If this hypothesis is correct, then it may be possible todevelop compounds targeting particular GABAA-R subtypes as, for example,selective anxiolytics with a diminished side effect profile. Thepyrazolo[1,5-a]-pyrimidine ocinaplon is anxioselective in both preclinicalstudies and in patients with generalized anxiety disorder, but does not exhibitthe selectivity between alpha1/alpha2-containing receptors for an anxioselective that is predicted by studies using transgenic mice. We hypothesized that thepharmacological properties of ocinaplon in vivo might be influenced by an active biotransformation product with greater selectivity for the alpha2 subunitrelative to alpha1. One hour after administration of ocinaplon, the plasmaconcentration of its primary biotransformation product, DOV 315,090, is 38% ofthe parent compound. The pharmacological properties of DOV 315,090 were assessed using radioligand binding studies and two-electrode voltage clampelectrophysiology. We report that DOV 315,090 possesses modulatory activity atGABAA-Rs, but that its selectivity profile is similar to that of ocinaplon. This implies that DOV 315,090 could contribute to the action of ocinaplon in vivo, butthat the anxioselective properties of ocinaplon cannot be readily explained by a subtype selective effect/action of DOV 315,090. Further inquiry is required toidentify the extent to which different subtypes are involved in the anxiolyticand other pharmacological effects of GABAA-R modulators.