Selective and Potent Monoamine Oxidase Type B Inhibitors: 2-Subtituted 5-Aryltetrazole Derivatives

Article abstract of DOI:10.1021/jm00024a006

Twenty new 2-(cyanoalkyl)tetrazoles (15 and 16) and twenty new 2-(hydroxyalkyl)tetrazoles (17 and 18) were synthesized and investigated in vitro for their abilities to inhibit selectivity rat brain monoamine oxidase (MAO) B over MAO A.Most of then were MAO B inhibitors and those bearing a sunstituted 4-(arylmethoxy)phenyl group in the position 5 of the tetrazole ring had IC50 values between 8 νM for 18d and 2 nM for 16a (30 nM for lazabemide) with a selectivity toward MAO B of 37000 for 16a.The reversibility of their inhibitory activity was demonstrated by in vitro dialysis tests.The 5-<4-(phenylmethoxy)phenyl>-2-(2-cyanoethyl)-tetrazole (16a) its derivative 16h and the 5-<4-(phenylmethoxy)phenyl>-2-(2-hydroxyethyl)-tetrazole (18a) and its derivative 18h were found to be potent, in vitro selective, and competitive MAO B inhibitors.Tetrazole 16a can be considered one of the most active and selective competitive MAO B inhibitors known up to now.This compound was selected for ex vivo experiments and shown to be a strong and reversible MAO B inhibitor with a short duration of action after oral administration at 5 mg/kg.The structure-activity approach gives rise to the great inportance of lipophilicity over electronic effects of the compounds in these series.