CGP 4718 A, a new potential antidepressant with a dual mode of action.

CGP 4718 A (4-[5-chloro-benzofuranyl-2-]-1-methylpiperidine HCl) was found to inhibit MAO A preferentially in vitro in a competitive manner. Assessment of its in vivo effects by an ex vivo approach showed it to be a relatively weak, reversible inhibitor of MAO A. There were also effects on MAO B but they were inferior by a factor of about 10. The onset of the inhibitory effects in rat liver and brain was rapid, being maximal in about 1 h following administration of CGP 4718 A p.o. The inhibition was of relatively short duration with the effects being undetectable 24 h after treatment. CGP 4718 A also inhibited the reuptake of serotonin (5-HT) in synaptosomes in vitro and ex vivo. Evidence for 5-HT uptake inhibition was also found by using the H 75/12 depletor model. Its in vitro and in vivo potency as a 5-HT uptake inhibitor was approximately the same as that of imipramine. The effects on MAO A and on 5-HT uptake occurred over a similar dose range (above 10 mg/kg p.o.) and also had a similar time course. No evidence for inhibitory effects on noradrenaline uptake was found in vivo.

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.