The interactions of monoamine oxidase with some derivatives of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
The interactions of a number of derivatives of the dopaminergic neurotoxin MPTP (1-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.
Sullivan
J P
JP
Department of Biochemistry, Trinity College, Dublin, Ireland.
Tipton
K F
KF
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008995:Monoamine Oxidase / Q000378:metabolism*
D004791:Enzyme Inhibitors; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase