Geometric isomers of styrlpiperidines selectively inhibit monoamine oxidase isoforms A and B.

DAMIJAN KNEZ; SIMON ZAKELJ; NORA MARIEL MARDER; STANISLAV GOBEC.; MATEJ SOVA; JURIJ TRONTELJ, ; JANKO KOS; ANJA PISLAR; NATALIA COLETTIS, ; CLAUDIA BINDA

Simposio; International Symposium of Medicinal Chemistry, 2 al 6 de septiembre, EFMC-YMCS 5th Young Medicinal Chemist Symposium, 6 al 7 de septiembre, Liubliana, Eslovenia.; 2018

Flavin-dependent oxidoreductases monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) are important targets in the therapy of several neurological disorders such as depression, Parkinson?s disease and Alzheimer?s disease.1,2 As a part of our screening program devoted to discovery of new compounds targeting neurodegenerative diseases, styrilpiperidines were found to inhibit MAO-A and MAO-B. A comprehensive series of over 90 novel styrilpiperidines was therefore synthesized by applying systematic structural modifications on the benzene ring and by replacing piperidine with smaller or bigger saturated rings. 1,4-Disubstituted N-propargylstyrilpiperidines with trans-vinyl linker connecting piperidine and benzene ring irreversibly inhibit human (h)MAO-B with low nanomolar IC50 values. On the other hand, cis isomers irreversibly inhibit human (h)MAO-A with high selectivity over hMAO-B (Figure 1A). In contrast, derivatives with prolonged substituents (butinyl/pentinyl) on piperidine nitrogen displayed reversible inhibition of hMAO-B. To characterize the mechanism of MAO inactivation, co-crystallization and UV/visible spectroscopy experiments were performed. Crystal structures of four N-propargylstyrilpiperidines in complex with human MAO-B were resolved, thus confirming irreversible covalent adduct with FAD cofactor (Figure 1B). Compounds are not cytotoxic to neuroblastoma SH-SY5Y cell line (EC50 > 100 µM) and display neuroprotective properties in cell based 6-hydroxydopamine model of Parkinson?s disease. They also display favorable in vitro pharmacokinetic parameters in terms of oral bioavailability and BBB permeability. Ex vivo experiments further on demonstrate MAO-A and MAO-B inhibition after i.p. and oral administration in mice brain homogenates. Importantly, selective hMAO-A inhibitor 3 (Figure 1A) shows antidepressant activity in mice after i.p. administration (0.3 mg/kg) in chronic 10-day treatment regime.