Studies on novel agents for depression and Parkinson’s disease. Potent pyrrole and indole monoamine oxidase inhibitors

Monoamine oxidase (MAO) is an outer mitochondrial membrane FAD containing enzyme found in nearly all tissues. On the basis of their substrate and inhibitor specificities, two isoforms have been described, the MAO-A and the MAO-B. MAOs are responsible for the major neurotrasmitter degrading in the central nervous system (CNS) and peripheral tissues. Because of their activity, MAO-A and MAO-B are involved in psychiatric and neurological disorders such as depression and Parkinson’s disease, respectively. Investigating moclobemide (1) and selegiline (2) structures, MAO-A and MAO-B selective inhibitors, respectively, we synthesized novel, simple, and highly selective pyrrole (3) and indole (4) MAO inhibitors.1 All compounds were tested on bovine brain mitochondria and the activities of MAO-A and MAO-B were determined by a fluorometric method. Novel compounds were active at micromolar and nanomolar concentrations on MAO-A and MAO-B; the selectivity index (SI) values [SI=Ki(MAO-A)/Ki(MAO-B)] ranged from >2500 to 0.0057. The biological results led us to discriminate between MAO-A and MAO-B selectivity in terms of structural differences. Molecular modeling studies permitted us to have an interaction model between 2-(N-methyl-N-benzylaminomethyl)-1H-pyrrole and MAO-B structure. References (1) Silvestri, R.; La Regina, G.; De Martino, G.; Artico, M.; Befani, O.; Palumbo, M.; Agostinelli, E.; Turini, P. Simple, potent, and selective pyrrole inhibitors of monoamine oxidase types A and B. J. Med. Chem. 2003, 46, 917-920.