Studies on 1,2,3,6-tetrahydropyridine derivatives as potential monoamine oxidase inactivators

Abstract

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 excellent substrate properties, MPTP is a 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, we have initiated studies to evaluate the enzymatic and biological properties of MPTP analogs bearing functional groups which are known to mediate the metabolism-dependent inactivation of this enzyme. This paper describes the synthesis, enzyme substrate/inhibitor properties, and neurotoxic/neuroprotective properties of 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine, the corresponding acyclic secondary amine (E)-4-cyclopropyl-2-phenyl-2-butene, and 4-cyclopropyl-1-methyl-1,2,3,6-tetrahydropyridine.