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.
Pharmaceutical Research Department, F. Hoffmann-La Roche & Co., Ltd., Basel, Switzerland.
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Da Prada
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Kettler
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Keller
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Burkard
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Muggli-Maniglio
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Haefely
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology*; D001679:Biogenic Amines / Q000032:analysis / Q000378:metabolism; D001792:Blood Platelets / Q000201:enzymology; D001921:Brain / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects*; D006168:Guinea Pigs; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D020912:Moclobemide; D008995:Monoamine Oxidase / Q000032:analysis; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000633:toxicity; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects
D000928:Antidepressive Agents; D001549:Benzamides; D001679:Biogenic Amines; D008996:Monoamine Oxidase Inhibitors; D011725:Pyridines; D011954:Receptors, Dopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D020912:Moclobemide