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

Abstract

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) that has been detected in the brains or normal laboratory rats, is biotranformed 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 rat of nigrostriatal cell loss associated with idiopathic Parkinson''s disease.