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.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives; D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D007189:Indans / Q000494:pharmacology; D008297:Male; D008454:Mazindol / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D011699:Putamen / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000633:toxicity*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D007189:Indans; D011725:Pyridines; C031967:rasagiline; C054016:1-methyl-4-cyclohexyl-1,2,3,6-tetrahydropyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008454:Mazindol; D004298:Dopamine