Design, synthesis, and biological evaluation of novel 4-substituted 1-methyl-1,2,3,6-tetrahydropyridine analogs of MPTP.

The exceptionally good MAO-B substrate properties of several 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) derivatives have prompted studies to evaluate the corresponding properties of tetrahydropyridines bearing heteroatom-linked groups at C-4. The 1-methyl-4-phenoxy-1,2,3,6-tetrahydropyridine analog proved to be an excellent MAO-B substrate. Unlike analogs bearing hydrocarbon substituents at C-4, the resulting dihydropyridinium metabolite did not undergo further oxidation to the pyridinium compound but rather underwent hydrolytic cleavage. This observation has led to studies designed to explore the possibility of developing novel, nontoxic derivatives of MPTP bearing potential pharmacologically active leaving groups at C-4. In this paper we report the results of synthetic and metabolic studies on a series of tetrahydropyridine analogs of MPTP with oxygen, sulfur, and carbamoyloxy derivatives on C-4 which serve as model compounds to evaluate the scope of this prodrug concept.