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 (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.
KeywordsMonoamine Oxidase Irreversible Inhibitor Dihydropyridine Derivative Tetrahydropyridine Ring Brain Monoamine Oxidase
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- Abell CW, Fritz RR, Patel NT, Shen RS, Gessner W, Brossi A (1986) Effects of MPTP and its metabolites on neurotransmitter degrading enzymes. In: Markey SP, Castagnoli N, Trevor AJ, Kopin IJ (eds) MPTP: a neurotoxin producing a Parkinsonian syndrome. Academic Press, New York, pp 219–233.Google Scholar
- Bradbury AJ, Costall B, Domeney AM, Jenner P, Marsden CD, Naylor RJ, Tan CCW (1985) The neurotoxic actions of MPTP in the rat are not confined to dopamine and the substantia nigra. Br J Pharmacol 86: 691p.Google Scholar
- Javitch JA, D’Amato RJ, Strittmater SM, Snyder SH (1985) Parkinsonism-inducing neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA 82: 2173–2177.PubMedCrossRefGoogle Scholar
- Pileblad E, Carlsson A (1985) Catecholamine uptake inhibitors prevent the neurotoxicity of 1-methyl-4-phenyl-tetrahydropyridine (MPTP) in mouse brain. Neuropsychophar-macology 24: 689–692.Google Scholar
- Singer TP, Salach JI, Castagnoli N, Trevor A (1986) Interactions of the neurotoxin I-methyl-4-phenyl-1,2,3,6-tetrahydropyridine with monoamine oxidases. Biochem J 135: 785–789.Google Scholar
- Tipton KF (1985) Determination of monoamine oxidase. Meth Find Exptl Clin Pharmacol 7: 361–367.Google Scholar
- Tipton KF, Fowler CJ, McCrodden JM, Strolin Benedetti M (1983) The enzyme-activated ireversible inhibition of type-B monoamine oxidase by 3-(4-[(3-chlorophenyl)-methoxy]-phenyl)-5-[(methylamino)methyl]-2-oxazolidinone methane sulphonate (compound MD 780236) and the enzyme-catalysed oxidation of this compound as competing reactions. Biochem J 209: 235–242.PubMedGoogle Scholar
- Tipton KF, McCrodden JM, Youdim MBH (1986) Oxidation and enzyme-activated irreversible inhibition of rat liver monoamine oxidase-B by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Biochem J 125: 521–524.Google Scholar
- Trevor AJ, Chiba K, Yu EY, Caldera PS, Castagnoli KP, Castagnoli N, Peterson L, Salach JI, Singer TP (1986) The metabolism of MPTP in vitro. The intermediate role of 2,3-MPDP+ and studies on its chemical and biochemical reactivity. In: Markey SP, Castagnoli N, Trevor AJ, Kopin IJ (eds) MPTP: a neurotoxin producing a Parkinsonian syndrome. Academic Press, New York, pp 161–172.Google Scholar