Intracerebral microdialysis neurotoxicity studies of quinoline and isoquinoline derivatives related to MPTP/MPP+.
The in vivo dopaminergic neurotoxicity of a series of quinoline and isoquinoline derivatives was assessed in rats using an intrastriatal microdialysis technique that measures the release of dopamine. The N-methyl quaternary salts of these two heterocyclic aromatic systems displayed about 10% of the potency of MPP+ in this assay. Furthermore, tetrahydroisoquinoline, which has been reported to be present in human brain, and N-methyltetrahydroisoquinoline were found to be MAO-B substrates, being oxidized at about 3% the rate of MPTP. Thus, although tetrahydroisoquinoline and N-methyltetrahydroisoquinoline are not neurotoxic, it is conceivable that the chronic endogenous formation of quaternary species could cause neuronal lesions that contribute to the etiology of idiopathic Parkinson's disease.
Booth
R G
RG
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
Castagnoli
N
N
Rollema
H
H
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D007546:Isoquinolines / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D011725:Pyridines / Q000378:metabolism / Q000633:toxicity*; D011726:Pyridinium Compounds / Q000378:metabolism / Q000633:toxicity*; D011804:Quinolines / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D007546:Isoquinolines; D011725:Pyridines; D011726:Pyridinium Compounds; D011804:Quinolines; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C037219:quinoline; C039109:isoquinoline; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine