The interactions of monoamine oxidase with some derivatives of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Summary

The interactions of a number of derivatives of the dopaminergic neurotoxin MPTP (l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) with monoamine oxidase (MAO) have been studied. The desmethyl derivative, 4-phenyl-1,2,3,6-tetrahydropyridine (PTP), was oxidised by MAO-B to form the corresponding dihydropyridine. Initial interaction with both forms of MAO was competitive. However the degree of inhibition of MAO-B, but not MAO-A, increased with time and became irreversible. Substitution of a methyl group at the 6-position of the heterocyclic ring of MPTP prevented it from acting as a substrate for MAO-B and greatly decreased its potency as an inhibitor of that form of MAO, although it remained a good competitive inhibitor of MAO-A. Replacement of the tetrahydropyridine ring of PTP by piperidine apparently abolished the ability to act as a substrate for MAO-B. The compound was however a competitive inhibitor of both forms of MAO. Substitution of a 3-(chlorophenyl)-methoxy-group at the 4’-position of this compound and PTP led to compounds which appeared to be devoid of substrate activity although they were potent, highly-selective, time-dependent inhibitors of MAO-B.