PRECLINICAL AND EARLY CLINICAL-STUDIES WITH BW-1370U87, A REVERSIBLE COMPETITIVE MONOAMINE OXIDASE-A INHIBITOR

BW 1370U87 is unique among potent inhibitors of monoamine oxidase-A (M AO-A) in that it contains no nitrogen. Like other MAO-A inhibitors, BW 1370U87 elevates neurotransmitter amines in the brain over the same d ose range at which it exhibits positive activities in animal models of depressive illness. However, BW 1370U87 differs from most other MAO i nhibitors in that its mechanism of action follows simple competitive k inetics, so that an unusually high concentration of tyramine in periph eral tissues may displace the inhibitor from MAO-A sites in the intest ine and liver. In addition, BW 1370U87 concentrations in brains of rat s appear much higher than in plasma, whereas extensive metabolism of t he parent compound in the liver produces weaker MAO-A inhibitors with the same type of competitive mechanism. Early phase-I safety trials at acute doses up to 2,000 mg of BW 1370U87 showed no adverse reactions, whereas MHPG in urine was decreased, indicating that in vivo inhibiti on of MAO-A was achieved in humans. Thus BW 1370U87 represents a new a gent with potential therapeutic application in depression and other CN S illnesses.