The proconvulsant effects of the GABAA α5 subtype-selective compound RY-080 may not be α5-mediated

RY-080 (ethyl 8-ethynyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate) is an imidazobenzodiazepine with 40–50-fold higher affinity for the benzodiazepine binding site of α5rather than α1-, α2or α3-containing GABAA receptors. Previous data describing RY-080 as being convulsant suggests that inverse agonists selective for the α5 subtype may not be suitable for clinical development. In the present study, we show that RY-080 possesses inverse agonism for the α1 and α5 subtypes of human recombinant GABAA receptors and whilst not convulsant it was proconvulsant. Hence, with pentylenetetrazole alone, the dose predicted to give tonic convulsions in 50% of the mice (ED50) was 108 mg/kg whereas in the presence of 1 and 10 mg/kg RY-080, the ED50s were 93 and 57 mg/kg, respectively. In vivo [ H]L-655,708 and [H]Ro 15–1788 binding assays showed that the subtype selectivity of RY-080 in vivo was 7–10-fold for α5-relative to α1and α2/α3containing receptors (respective ID50 values of 0.93, 9.7 and 6.2 mg/kg) and is therefore much lower than seen in vitro. Consequently, it is not possible to define a dose of RY-080 which gives high occupancy of the α5 subtype without binding to other subtypes and accordingly the proconvulsant effects of RY-080 cannot be attributed solely to the α5 subtype. © 2006 Published by Elsevier B.V.