Selective monoamine oxidase inhibitors. 3. Cyclic compounds related to 4-aminophenethylamine. Preparation and neuron-selective action of some 5-(2-aminoethyl)-2,3-dihydroindoles.

Abstract

Nine 5-(2-aminoethyl)-2,3-dihydroindole derivatives were synthesized and tested as monoamine oxidase (MAO) inhibitors in vitro and in vivo. All compounds were found to be selective MAO-A inhibitors in vitro, the most active ones, 5-[1-(2-aminopropyl)]-2,3-dihydro-4-methylindole acetate (3), 5-[1-(2-aminopropyl)]-4-chloro-2,3-dihydroindole acetate (5), 5-[1-(2-aminopropyl)]-2,3-dihydro-1-ethyl-4-methylindole tartrate (6), 5-[1-(2-aminopropyl)]-2,3-dihydro-1-ethyl-6-methylindole tartrate (7), and 5-[1-(2-aminobutyl)]-4-chloro-2,3-dihydroindole acetate (9) being equipotent with amiflamine, (S)-(+)-4-(dimethylamino)-2, alpha-dimethylphenethylamine. Some of the compounds, 3, 6, 5-[1-(2-aminopropyl)]-2,3-dihydroindole acetate (1), and 5-[1-(2-amino-2-methylpropyl)]-2,3-dihydroindole acetate (8), were found to be very potent inhibitors of MAO in serotonergic and/or noradrenergic nerve terminals in the rat brain in vivo, inhibiting MAO within these neurons at doses 1/10 of those required to inhibit MAO in other neurons or cells. Compound 1 was also a potent and selective inhibitor of MAO within dopaminergic nerve terminals in vivo. This neuron selectivity is due to the uptake of these compounds by the neuronal uptake mechanisms.