Time-dependent slowly-reversible inhibition of monoamine oxidase A by N-substituted 1,2,3,6-tetrahydropyridines.
Wichitnithad-W; O'Callaghan-JP; Miller-DB; Train-BC; Callery-PS
Bioorg Med Chem 2011 Dec; 19(24):7482-7492
A novel class of N-substituted tetrahydropyridine derivatives was found to have multiple kinetic mechanisms of monoamine oxidase A inhibition. Eleven structurally similar tetrahydropyridine derivatives were synthesized and evaluated as inhibitors of MAO-A and MAO-B. The most potent MAO-A inhibitor in the series, 2,4-dichlorophenoxypropyl analog 12, displayed time-dependent mixed noncompetitive inhibition. The inhibition was reversed by dialysis, indicating reversible enzyme inhibition. Evidence that the slow-binding inhibition of MAO-A with 12 involves a covalent bond was gained from stabilizing a covalent reversible intermediate product by reduction with sodium borohydride. The reduced enzyme complex was not reversible by dialysis. The results are consistent with slowly reversible, mechanismbased inhibition. Two tetrahydropyridine analogs that selectively inhibited MAO-A were characterized by kinetic mechanisms differing from the kinetic mechanism of 12. As reversible inhibitors of MAO-A, tetrahydropyridine analogs are at low risk of having an adverse effect of tyramine-induced hypertension.
Pyridines; Amines; Kinetics; Chemical-composition; Chemical-kinetics; Biochemical-analysis; Biochemical-indicators; Enzyme-activity; Enzyme-inhibitors; Medicinal-chemicals; Therapeutic-agents; Hypertension;
Author Keywords: Tetrahydropyridine; Monoamine oxidase; Time-dependent inhibition; Covalent;
Wisut Wichitnithad, Department of Basic Pharmaceutical Sciences and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA
Bioorganic & Medicinal Chemistry