Benzodiazepine receptor occupation and pharmacological effects of metaclazepam,a new benzodiazepine

The time course of benzodiazepine receptor occupation in mouse brain in vivo and the time courses of three pharmacological activities (anxiolytic/anticonvulsant, sedative, and muscle relaxant) were determined for metaclazepam and two of its putative minor metabolites, KC 3756 and KC 3757. Similar experiments were performed with diazepam as a reference compound. It was found that the in vivo receptor binding potency and the pharmacological activities of metaclazepam were three to four times less than those of diazepam, although the in vitro affinity of metaclazepam for the benzodiazepine receptor was only 1/100 that of diazepam. The in vivo benzodiazepine receptor binding potency and pharmacological activities of KC 3756 and KC 3757 were high (five to six times that of diazepam) and in good agreement with the in vitro affinity, K_i=0.93 and 1.4 nM, respectively. These findings suggest that the pharmacological activity of metaclazepam is partly regulated by the gradual formation of small quantities of highly active metabolites.