AbstractHP 370 4,9‐Dibromo‐6‐(4 methyl‐1‐piperaziny(l)benzo((b)pyrrolo[3,2,1‐jk][1,4 benzodiazepine]demonstrated preclinical activity indicative of clinical atypical antipsychotic activity, which may provide an advantage over current therapeutic agents. It was effective in blocking apomorphine‐induced climbing behavior in mice (ED50= 4.1 mg/kg i.p.; 1.6 mg/kg p.o), locomotion caused by direct application of dopamine to the nucleus accumbens in rats (ED50= 15.4 mg/kg i.p.), intracranial self‐stimulation in rats (ED50= 10.1 mg/kg i.p.), and pole‐climb avoidance in rats (ED50= 4.0 mg/kg p.o. avoidance; 10.6 mg/kg p.o. escape failures). HP 370 was relatively inactive in blocking aporomorphine‐induced stereotypy in rats (50% at 40 mg/kg, 33% at 20 mg/kg i.p.), relatively inactive in causing catalepsy in rats (50% at 40 mg/kg i.p.)m and was completely inactive in blocking stereotypy caused by the direct application of dopamine to the corpus striatum of rats (up to 80 mg/kg i.p.). Chronic administration of HP 370 caused supersensitivity to apomorphine in the climbing mouse test and in dopamine‐induced locomotion in rats, but not in dopamine‐induced stereotypy in rats. Acute administration of HP 370 caused and increase in the numberof active dopamine neurons sampled in both the ventral tegmental area and substantia nigra of rats, whereas chronic administration resulted in singnificantly fewer dopamine neurons found in the ventral tegmental area with no change from control levels observed for the substantia nigra. In a measure of social interaction in rats, HP 370 significantly increased the time spent interacting without altering overall activity, suggesting favorable effects on negative symptomatology. No in vivo anticholinergic activity was seen in the physostigmine lethality test in mice. In vivo blockade of alpha noradrenergic receptors was suggested by the inhibition of norepinephrine lethality in rats (50= 0.6 mg/kg i.p.). HP 370 displays an in vivo profile consistent with that of an atypical antipsychotic agent and is predicted to be clinically effective with fewer side effects than curr