Monoamine oxidase inhibition by moclobemide and 2-amino-ethyl carboxamide derivatives: mode of action and kinetic characteristics.

The selective, reversible inhibitors of monoamine oxidase (MAO) moclobemide and Ro 41-1049 (selective for MAO-A), as well as of Ro 16-6491 and Ro 19-6327 (selective for MAO-B) inhibited the enzyme with an initial competitive phase, followed by a time-dependent inhibition of MAO. Ro 41-1049, Ro 16-6491 and Ro 19-6327, being activated by MAO into reversible adducts, fit into the classification as mechanism-based inhibitors. Conversely, since no product formation was observed after incubation of tissue homogenates with moclobemide, this drug probably belongs to the class of the "slow-binding" MAO inhibitors.

From moclobemide to Ro 19-6327 and Ro 41-1049: the development of a new class of reversible, selective MAO-A and MAO-B inhibitors.

This study describes the serendipitous discovery of moclobemide, a short-acting MAO-A inhibitor which is in an advanced stage of clinical development as an antidepressant. The short duration of action of this MAO inhibitor containing a morpholine ring moiety is due to the complete reversibility (probably by metabolism of the inhibitory molecular species) of MAO-A inhibition. Since moclobemide is much more effective in vivo than expected from its in vitro activity, investigations to identify a possible metabolite(s) more active as MAO-A inhibitor than the parent compound were carried out. The study of the MAO inhibitory characteristics of several known and putative moclobemide metabolites did not allow the identification of a potent MAO-A inhibitor but led to the discovery of Ro 16-6491, a potent MAO-B inhibitor of novel chemical structure. Systematic chemical modification of the aromatic ring system of Ro 16-6491 finally provided Ro 19-6327 and Ro 41-1049 which are highly selective and reversible inhibitors of MAO-B and MAO-A, respectively. Tritiated derivatives of Ro 19-6327 and Ro 41-1049 were used in binding studies to elucidate their mechanisms of action and to study their cellular distribution by quantitative enzyme radioautography.

Neurochemical profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A.

Moclobemide belongs to a new generation of short-acting, reversible, monoamine oxidase (MAO) inhibitors. In vitro (rat brain homogenates) moclobemide inhibits MAO-A selectively with lower potency than many of the reference MAO inhibitors. However, when measured ex vivo in the rat, the potency of moclobemide is similar to that of reference compounds. In vivo the drug induces a dose-dependent, short-lasting (8-16 hr) and preferential inhibition of MAO-A in the brain and both MAO-A and MAO-B inhibition in extracerebral organs (liver, small intestine and kidney). In the extracerebral tissues of the rat moclobemide induces marked peripheral MAO-B inhibition due to rapid and extensive biotransformation of its morpholine ring. The active molecular species is probably the metabolite Ro 16-6491. The moderate MAO-B inhibition measured after moclobemide intake in human platelets indicates that only minor amounts of Ro 16-6491 are formed in humans. Virtually all metabolites of moclobemide so far identified have been tested in vitro and ex vivo in the rat and proved to be either equipotent or, mostly, less effective than moclobemide as MAO-A inhibitors. In liver homogenates of moclobemide-treated rats MAO-A activity recovers during dialysis or simple incubation at 37 degrees C, suggesting a biodegradation of moclobemide and/or the moclobemide-derived active metabolite(s) by MAO itself or a slow dissociation of the active inhibitory species from the enzyme. Similar to other MAO-A inhibitors, moclobemide induces an increase in the rat brain levels of 5-hydroxytryptamine, norepinephrine and dopamine and a concomitant decrease of their deaminated metabolites. These effects are of short duration (8-16 hr) and parallel the time course of MAO-A inhibition. Moclobemide administered subchronically down-regulates beta adrenoceptors as shown by binding experiments with brain cortical membranes using dihydroalprenolol as ligand. In vitro MAO inhibition by moclobemide is specific in that the compound does not affect other amine oxidases or monoamine uptake mechanisms; furthermore, it does not interact with various neurotransmitter or drug receptor sites. In conclusion, a large body of preclinical evidence characterizes moclobemide as a short-acting and reversible MAO-inhibitor. The neurochemical profile of moclobemide indicates clearly that this nonhydrazine nonhepatotoxic MAO-A inhibitor represents a novel and safe drug for treatment of affective disorders.