The monoamine oxidase inhibiting properties of CGP 11305 A.

CGP 11305 A (4-(5-methoxy-7-bromo-benzofuranyl)2-piperidine-HCl) inhibited serotonin (5-HT) deamination in brains and livers of pretreated rats. The ED50S were 1 and 0.7 mg/kg p.o., respectively. Phenylethylamine (PEA) deamination was only marginally affected up to doses of 100 mg/kg p.o. The duration of action of the compound was less than 48 h, and its effects did not cumulate after repeated oral treatment. Kinetic studies in mitochondrial preparations from both tissues of the rat showed that with both 5-HT and PEA as substrates the inhibition was of the competitive type when the enzyme preparation and the inhibitor were not preincubated prior to assay. These properties suggested a reversible interaction of the compound with the enzyme. However, in 'ex vivo' studies, the inhibitory activity of CGP 11305 A was not lost by dilution or dialysis of homogenates from pretreated animals and the inhibitor could not be displaced by 5-HT. Similar results were obtained when CGP 11305 A was preincubated with mitochondria or homogenates from rat liver in vitro, indicating an irreversible interaction. The apparent contradiction between the short duration of the MAO inhibitory effect of CGP 11305 A in vivo and the seemingly irreversible interaction with the enzyme under ex vivo and in vitro conditions has not yet been resolved, although a number of possible mechanisms have been considered. The short duration of action and the lack of cumulative effects of this powerful and selective monoamine oxidase-A inhibitor in vivo might, however, result in it being a valuable antidepressant.