title: Time-dependent slowly-reversible inhibition of monoamine oxidase A by N-substituted 1,2,3,6-tetrahydropyridines.
abstract: 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, mechanism-based 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.
authors.affiliation: Department of Basic Pharmaceutical Sciences and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Wisut
authors.initials: W
authors.lastname: Wichitnithad
authors.forename: James P
authors.initials: JP
authors.lastname: O'Callaghan
authors.forename: Diane B
authors.initials: DB
authors.lastname: Miller
authors.forename: Brian C
authors.initials: BC
authors.lastname: Train
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Callery
mesh_terms: D000818:Animals; D001894:Borohydrides / Q000378:metabolism; D001921:Brain / Q000187:drug effects; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D019163:Reducing Agents / Q000378:metabolism
chemical_list: D001894:Borohydrides; D008996:Monoamine Oxidase Inhibitors; D011725:Pyridines; D019163:Reducing Agents; C025364:sodium borohydride; D008995:Monoamine Oxidase