Studies on 1,2,3,6-tetrahydropyridine derivatives as potential monoamine oxidase inactivators.
The Parkinsonian-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and close structural analogs are the only known cyclic tertiary amines with good monoamine oxidase substrate properties. In addition to its excellent substrate properties, MPTP is a mechanism-based inactivator of monoamine oxidase B (MAO-B). In an attempt to exploit the special interactions between this cyclic tertiary allylamine and MAO-B, we have initiated studies to evaluate the enzymatic and biological properties of MPTP analogs bearing functional groups which are known to mediate the metabolism-dependent inactivation of this enzyme. This paper describes the synthesis, enzyme substrate/inhibitor properties, and neurotoxic/neuroprotective properties of 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine, the corresponding acyclic secondary amine (E)-4-cyclopropyl-2-phenyl-2-butene, and 4-cyclopropyl-1-methyl-1,2,3,6-tetrahydropyridine.
Hall
L
L
Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg 24061.
Murray
S
S
Castagnoli
K
K
Castagnoli
N
N
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002073:Butanes / Q000138:chemical synthesis / Q000633:toxicity; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000633:toxicity; D004298:Dopamine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology
D002073:Butanes; D003521:Cyclopropanes; D008996:Monoamine Oxidase Inhibitors; C078252:1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine; C078253:4-cyclopropyl-2-phenyl-2-butene; C078254:4-cyclopropyl-1-methyl-1,2,3,6-tetrahydropyridine; D012642:Selegiline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine