BEHAVIORAL-EFFECTS AND DOPAMINE ANTAGONIST PROPERTIES OF N-ALKYLAMINOBENZAZEPINES

Blockade of dopamine D-1 receptors has been suggested as a novel thera peutic approach to psychotic disorders and to psychomotor stimulant de pendencies. Peripheral D-1 receptors have also been implicated in the acute lethal effects of cocaine. Attempts to synthesize a D-1 antagoni st that does not penetrate the central nervous system led to the disco very of a novel series of N-alkylaminobenzazepine D-1 antagonists. In the present study, the most potent compound of that series, JHS 271, s uppressed locomotor activity, and blocked cocaine-stimulated activity, apomorphine-induced stereotypies, and the lethal effects of cocaine i n mice. Structural analogs of JHS 271 were also evaluated in selected assays. Potencies in these tests demonstrated a significant positive c orrelation with affinities for the D-1 receptor. These results implica te D-1 receptor blockade as a mechanism of action for JHS 271 and rela ted compounds. Comparative studies of central vs. systemic administrat ion and determination of blood/brain concentrations indicated that JHS 271, like SCH 23390, can readily access central sites upon systemic a pplication. (C) 1996 Wiley-Liss, Inc.