FA-70, a novel selective and irreversible monoamine oxidase-A inhibitor: Effect on monoamine metabolism in mouse cerebral cortex

A series of indolealkylamine derivatives has been previously designed and e valuated with the aim of finding the most potent and selective novel monoam ine oxidase (MAO) inhibitors to be used in the therapy of neurological and affective disorders. Among them, FA70, a 5-hydroxy-indolealkylamine derivat ive, has been characterized in vitro as a potent, irreversible, and mechani sm-based inhibitor of the MAO-A isoform. The comparison with clorgyline, an alyzed under the same experimental conditions, confirmed FA70 as the most p otent MAO-A inhibitor. The ex vivo effect of FA70 on MAO activity in mouse cerebral cortex was similar to that observed in vitro, showing more efficac y than in peripheral tissues. The ex vivo effect of FA70 on amine metabolis m also was evaluated after acute and chronic treatment, and the results sho wed that between both MAO isoforms, MAO-A is the only one responsible for m onoamine metabolism in this region of the brain. The ex vivo effect of FA70 on dopamine content was correlated with the activation effect on tyrosine hydroxylase activity, the enzyme responsible for the regulation of the limi ting step in catecholamine synthesis.