MOLECULAR-SIZE AND FLEXIBILITY AS DETERMINANTS OF SELECTIVITY IN THE OF OXIDATION OF N-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE ANALOGS MONOAMINE OXIDASE-A AND OXIDASE-B

The introduction of a methylene bridge between the phenyl and tetrahyd ropyridyl moieties of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MP TP) results in increased selectivity for monoamine oxidase B (MAO B) o ver monoamine oxidase A (MAO A). However, lengthening of this bridge r esults in a total loss of selectivity. In the present study, a number of isomeric 4-naphthyl-, 4-(naphthylalkyl)-,4-thienyl-, and 4-(thienyl alkyl)tetrahydropyridines, conformationally restrained and flexible an alogs of MPTP, were synthesized and evaluated as potential selective s ubstrates of MAO A and B. In terms of the parameter (turnover number)/ K(m), the bulky naphthyl analogs were invariably better substrates of MAO A than kynuramine, the reference substrate for this enzyme. In add ition, all naphthyl analogs, regardless of conformational mobility, we re more effective substrates of MAO A than MAO B. Similarly, all thien yl analogs were found to be more effective substrates of MAO B. In con trast to the naphthalenes, the conformationally restrained thiophenes 9a and 10a were found to be poor substrates of MAO B, relative to benz ylamine, the reference substrate. These results suggest that the selec tivity of these compounds for either MAO A or B is determined by the c omplex interplay of molecular size and flexibility. In this interplay, either one of these two factors may predominate.