Newer aspects of the reversible inhibitor of MAO-A and serotonin reuptake, brofaromine.

1. The reasons for developing second-generation MAOI are outlined. The expected advantage of reversibility as a safety valve with respect to tyramine potentiation is discussed. 2. Earlier data from in vitro and some ex vivo experiments had suggested an irreversible interaction of brofaromine with MAO-A, whereas the short duration of action, the absence of cumulation of effect and the displaceability by endogenously released substrates indicated reversibility. This apparent conflict could be solved by the demonstration that brofaromine behaves as a tight-binding reversible inhibitor. 3. In in vivo binding experiments with [3H]brofaromine given i.v., clorgyline, brofaromine and moclobemide were shown to dose-dependently displace the radioligand from MAO-A in the rat brain when administered after it. In corresponding experiments in the rat intestine in which the radioligand was administered p.o., similar results were obtained. Moreover, tyramine given orally in pressor doses after the radioligand also displaced it, confirming the idea that reversibility could act as a safety valve. 4. The evidence from animal and human experiments is presented that brofaromine is safer than classical MAO inhibitors with respect to tyramine potentiation. 5. Based on computer simulations, it is suggested that reduced liability of the new MAO reversible inhibitors to cause tyramine potentiation may potentially be linked to a reduced therapeutic efficacy. 6. The evidence is discussed that 5-HT uptake inhibition by brofaromine is relevant in its therapeutic effect in humans and may synergize with MAO-A inhibition, thus enhancing the impact of the latter on serotonergic transmission.