Pharmacological characterization of benzodiazepine receptors in the brain

Abstract

Receptors in rat brain membranes which specifically bind ³H-diazepam were characterized pharmacologically using reference substances representing several pharmacological classes of drugs. Of 28 benzodiazepines tested, several “classical” ones (diazepam, clonazepam, lorazepam, oxazepam, nitrazepam, flurazepam, bromazepam and chlorazepate) with known clinical efficacy, as well as three newer “triazolo” benzodiazepines (estazolam, U 35,005, U 31,957), one new “imidazolo” benzodiazepine, U 31,219, and one new 2-carbamoylmethylene-benzodiazepine, displaced ³H-diazepam binding at low concentrations (K_i = 1–60 nM). For these benzodiazepines there was a statistically significant correlation between K_i values for displacement and ED₅₀ (or MED) values in several pharmacological tests predictive of anxiolytic activity in man. More than 100 nonbenzodiazepines, representing 22 distinct pharmacological classes as well as 14 presumed neurotransmitters in the CNS, including 4 peptides, were much weaker as ³H-diazepam displacers (K_i > 0.1 nM). These results that in vitro ³H-diazepam binding represents the physiologically relevant binding to hitherto unknown receptors in the CNS.