Flexible N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine analogues: synthesis and monoamine oxidase catalyzed bioactivation.
Eighteen analogues of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were synthesized and evaluated as substrates of monoamine oxidase. In general, the flexible analogues, characterized by the presence of a methylene (or ethylene) bridge between the aryl/heteroaryl and tetrahydropyridyl moieties, were better substrates of the enzyme than the conformationally restricted MPTP. It is suggested that the increased oxidative activity of these flexible analogues reflects enhanced binding due to the ability of the C-4-aryl/heteroaryl substituent to gain access to a hydrophobic pocket within the substrate binding site.
Efange
S M
SM
Department of Radiology, University of Minnesota, Minneapolis 55455.
Michelson
R H
RH
Remmel
R P
RP
Boudreau
R J
RJ
Dutta
A K
AK
Freshler
A
A
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001665:Binding Sites; D001711:Biotransformation; D001921:Brain / Q000201:enzymology / Q000648:ultrastructure; D055598:Chemical Phenomena; D002621:Chemistry; D007700:Kinetics; D008928:Mitochondria / Q000201:enzymology; D008968:Molecular Conformation; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010293:Pargyline / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D008996:Monoamine Oxidase Inhibitors; D010293:Pargyline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase