Studies on semirigid tricyclic analogs of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

• Published in: Journal of medicinal chemistry Vol. 32; no. 2; pp. 473 - 477
• Main Authors: Booth, Raymond G, Trevor, Anthony, Singer, Thomas P, Castagnoli, Neal
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.02.1989
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Carbolines - chemical synthesis; Carbolines - metabolism; Carbolines - toxicity; Chemistry; Corpus Striatum - drug effects; Dopamine - analysis; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Male; Mice; Mice, Inbred C57BL; Monoamine Oxidase - pharmacology; Monoamine Oxidase Inhibitors - pharmacology; Organic chemistry; Oxidation-Reduction; Preparations and properties; Pyridines - metabolism; Pyridines - toxicity; Structure-Activity Relationship; Substantia Nigra - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00122a031

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.