DOPAMINE UPTAKE INHIBITORY CAPACITIES OF BETA-CARBOLINE AND 3,4-DIHYDRO-BETA-CARBOLINE ANALOGS OF N-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE (MPTP) OXIDATION-PRODUCTS

Potentially endogenous β-carboline and 3,4-dihydro-β-carboline alkaloidal compounds were compared, generally as 2-methylated (quaternary) and normethylated pairs, to the neurotoxin, 1-methyl-4-phenyl-dihydropyridinium ion (MPP+), with respect to inhibition of [3H]dopamine uptake into rat striatal synaptosomal preparations. Although less potent than MPP+, several compounds displayed IC50 values for inhibition in the moderate range (12-24 μM). Notably, quaternization generally did not improve inhibitory potency, and the 3,4-dihydro-compounds often were more effective inhibitors than their heteroaromatic analogs. The partially competetive nature of inhibition by one of the more effective pairs, 2-methyl-harmine and harmine, was consistent with uptake of the beta-carbolines by the synaptosomal dopamine uptake system, as was the fact that the accumulation of 2-[14C]methyl-harmine was significantly reduced by low Na+ media and by nomifensine, a potent inhibitor of the dopamine transporter. When viewed with reports that certain 2-methyl-β-carbolines show MPP+-like toxicity in vitro and in vivo, these studies support the proposal that a mammalian β-carbolinium compound may be taken up by nigrostriatal neurons and provoke the neuronal degeneration underlying Parkinson's disease. © 1990.