Studies on 4-benzyl-1-methyl-1,2,3,6-tetrahydropyridine, a nonneurotoxic analogue of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Previous reports indicate that 4-benzyl-1-methyl-1,2,3,6-tetrahydropyridine (BMTP), the benzyl analogue of the Parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is not neurotoxic in the C-57 black mouse even when administered at a dose 10 times greater than the dose of MPTP required to cause an 85% depletion of neostriatal dopamine. Intrastriatal microdialysis in the rat with the corresponding 4-benzyl-1-methylpyridinium ion BMP+ for 60 min, however, causes nerve terminal destruction similar to that observed following a 15-min perfusion with the 1-methyl-4-phenylpyridinium ion MPP+, the monoamine oxidase B (MAO-B) generated metabolite derived from MPTP. With the aid of purified beef liver MAO-B and synthetic standards, we observed the efficient and quantitative conversion of BMTP to the corresponding 2,3-dihydropyridinium intermediate BMDP+, which underwent further, but incomplete, oxidation to BMP+. These MPTP-type properties point to in vivo effects, such as pharmacokinetic parameters and/or alternative metabolic pathways, to account for BMTP's lack of neurotoxicity.
Naiman
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N
Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg 24061.
Rollema
H
H
Johnson
E
E
Castagnoli
N
N
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002417:Cattle; D006224:Cricetinae; D008099:Liver / Q000201:enzymology / Q000648:ultrastructure; D020267:MPTP Poisoning; D008930:Mitochondria, Liver / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism; D010084:Oxidation-Reduction; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D051381:Rats
C071518:4-benzyl-1-methyl-1,2,3,6-tetrahydropyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase