OVERVIEW OF THE CNS PHARMACOLOGY OF BW-1370U87 - A CHEMICALLY NOVEL, REVERSIBLE, SELECTIVE MAO-A INHIBITOR WITH POTENTIAL TO BE A NEW ANTIDEPRESSANT DRUG

BW 1370U87 is a potent, reversible, selective inhibitor of rat and hum an brain MAO-A with a competitive mechanism of action. The ED50 of BW 1370U87 for inhibition of MAO-A in rat brain is 8 mg/kg after oral adm inistration, and the duration of action exceeds 7 hr. The ED80 dose fo r inhibition of MAO-A (20 mg/kg) elevates NE, DA, and 5-HT levels in b rains of rats without significantly potentiating the blood pressure ef fects of a 15 mg/kg oral dose of tyramine. This dose of tyramine, extr apolated to man, exceeds the amount that could be consumed at one time from dietary sources. No inhibition of MAO-B has been observed with B W 1370U87 either in vitro or ex vivo. BW 1370U87 was effective in the 5-hydroxytryptophan potentiation test over the dose range that produce d MAO-A inhibition in brain in both rats and mice, and it reduced swim stress induced immobility in the Porsolt test. The compound has posit ive effects on abnormal social behavior produced by early social depri vation in the rhesus monkey. BW 1370U87 had no adverse cardiovascular effects in dogs or rats. It also had no significant pharmacological ef fects on various isolated tissue preparations and did not cause change s in the neuronal transport or the receptor systems which mediate the antidepressant effects or side effects of the tricyclic antidepressant s. An acute oral dose 100 times that which produced an 80% inhibition of brain MAO-A exhibited no signs of toxicity. BW 1370U87 appears to b e a safe reversible MAO-A inhibitor with potential for treating depres sion, anxiety conditions, panic, phobias, obsessive compulsive behavio rs, and borderline personality disorders.