Irazepine, a noncompetitive, irreversible inhibitor of ³H- diazepam binding to benzodiazepine receptors [11]

THE identification and characterisation of stereospecific, high-affinity binding sites for benzodiazepines in the mammalian CNS has been described both in vivo^1-3 and in vitro^4-6. The correlations obtained between the in vitro affinities of a series of benzodiazepines for these binding sites and their clinical potencies as muscle relaxants², anxiolytics⁶ and anticonvulsants⁶ strongly suggest that these sites are pharmacological receptors mediating the therapeutic actions of the benzodiazepines. Benzodiazepines such as clonazepam, oxazepam and flurazepam are rapidly reversible, competitive inhibitors of ³H-diazepam binding to synaptosomal membranes^7,8. Competitive inhibition of ³H-diazepam binding has also been observed with the triazolopyridazines, which possess both anticonvulsant and anxiolytic activity⁹, and with the purines inosine and hypoxanthine ^10,11, which may be endogenous ligands to the benzodiazepine receptor^10-14. The development of noncompetitive, irreversible ligands has been invaluable in the characterisation, isolation and purification of both peripheral and central neurotransmitter receptors¹⁵, and may also prove useful for studying the benzodiazepine receptor. We now report the synthesis of a novel benzodiazepine, irazepine, which acts as a noncompetitive, irreversible inhibitor of ³H-diazepam binding to synaptosomal membranes.