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 beta-carboline and 3,4-dihydro-beta-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 microM). 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 competitive 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-beta-carbolines show MPP+-like toxicity in vitro and in vivo, these studies support the proposal that a mammalian beta-carbolinium compound may be taken up by nigrostriatal neurons and provoke the neuronal degeneration underlying Parkinson's disease.
Drucker
G
G
Department of Biochemistry and Biophysics, Loyola University Stritch School of Medicine, Maywood, IL 60153.
Raikoff
K
K
Neafsey
E J
EJ
Collins
M A
MA
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D002243:Carbolines / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000493:pharmacokinetics*; D006247:Harmine / Q000494:pharmacology; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D002243:Carbolines; D014179:Neurotransmitter Uptake Inhibitors; D006247:Harmine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine