Comparative anticonvulsant activity of the GABAkine KRM‐II‐81 and a deuterated analog

Abstract

AbstractA series of imidazodiazepines has been developed that possess reduced sedative liabilities but retain efficacy in anticonvulsant screening models. The latest of these compounds, (5‐(8‐ethynyl‐6‐(pyridin‐2‐yl)‐4H‐benzo[f]imidazole[1,5‐α][1,4]diazepin‐3‐yl) oxazole known as KRM‐II‐81) is currently awaiting advancement into the clinic. A deuterated structural analog (D5‐KRM‐II‐81) was made as a potential backup compound and studied here in comparison to KRM‐II‐81. In the present study, both compounds significantly prevented seizures in mice induced by 6 Hz (44 mA) electrical stimulation without significantly altering motoric function on a rotarod after intraperitoneal administration. Both compounds also significantly prevented clonic seizures, tonic seizures, and lethality induced by pentylenetetrazol in mice when given orally. D5‐KRM‐II‐81 had a slightly longer duration of action against clonic and tonic seizures than KRM‐II‐81. Oral administration of 100 mg/kg of either KRM‐II‐81 or D5‐KRM‐II‐81 was significantly less disruptive of sensorimotor function in mice than diazepam (5 mg/kg, p.o.). The present report documents that D5‐KRM‐II‐81 represents another in this series of imidazodiazepines with anticonvulsant activity at doses that do not impair sensorimotor function.