1-Methyl-4-cyclohexyl-1,2,3,6-tetrahydropyridine (MCTP): an alicyclic MPTP-like neurotoxin

1-Methyl-4-cyclohexyl-1,2,3,6-tetrahydropyridine (MCTP), an analog of MPTP, was found to be an MPTP-like neurotoxin. MCTP administration caused extensive losses of neostriatal dopamine and its major metabolites in male Swiss-Webster mice. Under similar experimental conditions, MCTP was approximately as potent as MPTP. Like MPTP, MCTP was a good substrate for monoamine oxidase-B (MAO-B) and its neurotoxicity was prevented in mice by AGN-1135, a selective inhibitor of MAO-B. The neurotoxicity of MCTP and of MPTP was also prevented by the dopamine uptake inhibitor mazindol. 1-Methyl-4-cyclohexylpyridinium ion (MCP+), the 4-electron oxidation product of MCTP, caused release of previously accumulated [3H]dopamine from mouse neostriatal synaptosomes. This release was blocked by mazindol, which indicates that MCP+, like 1-methyl-4-phenylpyridinium ion (MPP+), the 4-electron oxidation product of MPTP, is a substrate for the dopamine transport system. Like MPP+, MCP+ was found to inhibit the mitochondrial oxidation of NADH-linked substrates. It appears that conjugation between the tetrahydropyridine ring and a 4-substituent is not a requirement for an MPTP analog to possess neurotoxicity.