Thesis (Ph. D.)--Virginia Polytechnic Institute and State University, 1993. / Vita. Abstract. Includes bibliographical references (leaves 276-302). Also available via the Internet.

The Parkinsonian-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and close structural analogs are the only known cyclic tertiary amines with good monoamine oxidase substrate properties. In addition to its substrate properties, MPTP is a weak mechanism-based inactivator of monoamine oxidase-B (MAO-B). In an attempt to exploit the special interactions between this cyclic tertiary allylamine and MAO-B, studies were initiated to develop novel mechanism-based inactivators of this flavoenzyme. Analogs of MPTP bearing a variety of functional groups at either N or the C(4) position have been synthesized and their interactions with purified MAO-B have been characterized. The substituents selected included functionalities which were considered potential sources of enzyme generated electrophilic or radical intermediates that might alkylate and inactivate the enzyme. None of the C(4)-substituted compounds displayed significant enzyme inhibitor properties while the 4-phenyl-I-propargyl analog was a good mechanism-based inactivator of MAO-B but not MAO-A. The 4-phenyl-1-propyl derivative showed significant turnover with MAO-B suggesting that previous reports regarding the lack of substrate properties of MPTP analogs bearing N-substituents larger than methyl must be viewed with caution. The MAO-A and B generated dihydropyridinium metabolite derived from 1-methyl-4-phenoxy-1,2,3,6-tetrahydropyridine was | observed to undergo rapid hydrolytic cleavage to yield phenol and 1-methyl-2,3-dihydropyridone, a chromophoric species that could be monitored spectrophotometrically. This reaction sequence was exploited to probe the active site of MAO-A and MAO-B with a variety of C(4)-aryloxytetrahydropyridine analogs bearing groups of different steric bulk on the aryloxy moiety. Almost all of the compounds displayed good to excellent substrate properties with MAO-A and MAO-B. In contrast to previous claims, these results argue that the active sites of both MAO-A and MAO-B will accommodate tetrahydropyridine derivatives bearing bulky groups at C-4. Consequently other factors are likely to contribute to substrate selectivity. The results described in this thesis provide evidence that a variety of disubstituted tetrahydropyridine derivatives are good to excellent substrates for MAO-A and MAO-B. The new insights gained in terms of structure-activity relationships with the compounds studied here should set the stage for the design of other tetrahydropyridine analogs with therapeutic potential. The localization of MAO-A and MAO-B in specific cell types within the nervous system makes particularly attractive the possibility of designing tetrahydropyridine based prodrugs which will undergo bioactivation in selected cells in the nervous system resulting in the liberation of the pharmacologically active species. / Ph. D.