Studies on semirigid tricyclic analogues of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
The tetrahydro-beta-carboline derived from the condensation of N-methyltryptamine and formaldehyde, a semirigid tricyclic analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) tha has been detected in the brains of normal laboratory rats, is biotransformed in a monoamine oxidase B (MAO-B) catalyzed reaction to the corresponding dihydro compound at a rate that is approximately 0.5% of that observed with MPTP. The corresponding tetrahydroindenopyridine in which the double bond beta,gamma to the nitrogen atom retains allylic character is a somewhat better MAO-B substrate. The steric bulk of the nitrogen and methylene bridges in addition to ring strain present in the proposed carbon-centered radical intermediates derived from these types of tricyclic structures may contribute to their relatively poor MAO-B substrate properties. Although no MPTP-like neurotoxic properties were observed following acute administration of the test compounds to mice, we speculate that the chronic accumulation of beta-carbolinium type metabolites could contribute to the rate of nigrostriatal cell loss associated with idiopathic Parkinson's disease.
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143-0446.
R G
RG
Booth
A
A
Trevor
T P
TP
Singer
N
N
Castagnoli
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D002243:Carbolines / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008995:Monoamine Oxidase / Q000494:pharmacology; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010084:Oxidation-Reduction; D011725:Pyridines / Q000378:metabolism / Q000633:toxicity*; D013329:Structure-Activity Relationship; D013378:Substantia Nigra / Q000187:drug effects*
D002243:Carbolines; D008996:Monoamine Oxidase Inhibitors; D011725:Pyridines; C009804:tryptoline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D004298:Dopamine