HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

[Tetrahydroisoquinoline derivatives as possible Parkinson's disease-inducing substances].

Abstract
Parkinson's disease (PD) is believed to be induced by the interaction of genetic predisposition and environmental factors, and a type of neurotoxin is proposed to be one of the environmental factors. We designed and synthesized a molecule, 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) as a possible PD-eliciting neurotoxin and evaluated its characteristics relevant to PD. 1BnTIQ is an endogenous amine in the brain and the 1BnTIQ content increases in the patients with PD. Repeated administration of 1BnTIQ induced PD-like symptoms in monkeys and mice. 1BnTIQ was biosynthesized from 2-phenylethylamine and phenylacetaldehyde, which is a metabolite of 2-phenylethylamine, and used in in vivo and in vitro studies. 1BnTIQ inhibited [3H] dopamine uptake in HEK293 cells which stably express dopamine transporter. 1BnTIQ also inhibited NADH-ubiquinone oxidoreductase (complex I) in the mitochondrial respiratory chain. Next, we assessed 1BnTIQ neurotoxicity in the organotypic coculture of the ventromedial portion of the mesencephalon and striatum. 1BnTIQ decreased the dopamine content in the mesencephalon in both dose- and time-dependent manners and it irreversibly reduced the dopamine content. Furthermore, it caused morphological changes in tyrosine hydroxylase-positive cells in the mesencephalon and reduced the number of cells. 1-(3',4'-Dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3'4'DHBnTIQ) is also an endogenous parkinsonism-inducing 1BnTIQ derivative. In vivo and in vitro studies revealed that 3'4'DHBnTIQ was O-methylated by soluble catechol-O-methyltransferase (COMT). The result that COMT inhibitor suppressed 3'4'DHBnTIQ neurotoxicity suggests that 3'4'DHBnTIQ is metabolically activated by COMT to exert toxic effects.
AuthorsYaichiro Kotake
JournalYakugaku zasshi : Journal of the Pharmaceutical Society of Japan (Yakugaku Zasshi) Vol. 122 Issue 11 Pg. 975-82 (Nov 2002) ISSN: 0031-6903 [Print] Japan
PMID12440154 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
Chemical References
  • Isoquinolines
  • Neurotoxins
  • Tetrahydroisoquinolines
  • NADH, NADPH Oxidoreductases
  • Catechol O-Methyltransferase
  • Electron Transport Complex I
  • Dopamine
  • 1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline
Topics
  • Animals
  • Brain (drug effects, metabolism)
  • Catechol O-Methyltransferase (physiology)
  • Cells, Cultured
  • Dopamine (metabolism)
  • Electron Transport Complex I
  • Humans
  • Isoquinolines (metabolism, toxicity)
  • Mice
  • Mitochondria (enzymology)
  • NADH, NADPH Oxidoreductases (antagonists & inhibitors)
  • Neurotoxins (metabolism, toxicity)
  • Parkinson Disease (etiology)
  • Tetrahydroisoquinolines

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: