Alkaloids in mammalian tissues. 2. Synthesis of (+)- and (-)-1-substituted-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines

Deng

et al. 1997

Endogenous isoquinolines with and without catechol structure have been proposed to be neurotoxins specific for dopamine neurons. In this paper they were examined for the cytotoxicity of human dopaminergic neuroblastoma SH-SY5Y cells. The cytotoxicity was quantitatively determined using Alamar Blue assay, by which the reduction-oxidation potency in the living cells can be measured spectrometrically. 1,2-Dimethyl-6,7-dihydroxyisoquinolinium ion [1,2-DMDHIQ+], an oxidation product of a parkinsonism-inducing isoquinoline, 1(R),2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahroisoquinoline [N-methyl-(R)salsolinol, NM(R)Sal] was found to be the most potent toxin among isoquinolines examined. In general, catechol isoquinolines were more toxic than isoquinolines without catechol structure. With and without catechol structure, the oxidized isoquinolinium ion having methyl groups at C-1 and N-2 positions proved to be more cytotoxic than the simple isoquinolines. The involvement of 1,2-DMDHIQ+ to the neurotoxicity of NM(R)Sal was suggested and discussed.

Section: Methodsmentioning

confidence: 99%

Cytotoxicity of endogenous isoquinolines to human dopaminergic neuroblastoma SH-SY5Y cells

Takahashi

Deng

et al. 1997

“…The (R)-and (S)-enantiomer of Sal and NMSal were synthesized according to Teitel et al (1972), and DMDHIQ + to Bembenek et al (1990). DA, L-DOPA, and homovanillic acid (HVA) and other chemicals were purchased from Sigma (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Stereospecific occurrence of a parkinsonism-inducing catechol isoquinoline, n-methyl(R)salsolinol, in the human intraventricular fluid

Narabayashi

Dostert³

et al. 1996

N-Methyl(R)salsolinol, an endogenous neurotoxin, has been proposed to be closely involved in the pathogenesis of Parkinson's disease. The selective toxicity to dopaminergic neurons was strictly limited for (R)-enantiomer of N-methylsalsolinol. Its precursor, (R)salsolinol was enzymatically synthesized from dopamine and acetaldehyde in human. However, it has never been examined whether a non-enzymatic reaction produces racemic salsolinol derivatives from dopamine especially in patients under L-DOPA therapy. To clarify the point, their contents were examined in intraventricular fluid from parkinsonian patients administrated with L-DOPA. Only (R)-enantiomer of N-methylsalsolinol and very low concentration of salsolinol could be detected. The results suggest that N-methyl(R)salsolinol synthesis may not depend on dopamine level, but on the activity of enzymes related to its synthesis and/or catabolism. The results are discussed in relation to pathogenesis Parkinson's disease.

“…Clorgyline was kindly donated by May and Baker Co. (Dagenham, U.K.) and (-)-deprenyl by Dr. J. Knoll, Department of Pharmacology, Semmelweis University of Medicine (Budapest, Hungary). (R) and (S)SAL, NorSAL, and their N-methylated compounds were synthesized according to Teitel et al (1972). Kynuramine was purchased from Sigma (St. Louis, MO, U.S.A.).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of type A and B monoamine oxidase by 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines and their N-methylated derivatives

Minami

Dostert

et al. 1993

6,7-Dihydroxy-1,2,3,4-tetrahydroisoquinoline (norsalsolinol) and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), and their N-methylated derivatives were found to inhibit type A and B monoamine oxidase isolated from human brain synaptosomal mitochondria. N-Methyl-norsalsolinol, (R) and (S) enantiomer of salsolinol, and N-methyl-salsolinols inhibited type A monoamine oxidase competitively to the substrate, kynuramine, and R enantiomers were more potent inhibitors than S enantiomers. The inhibition was reversible. Norsalsolinol induced positive cooperativity toward kynuramine. Both norsalsolinol and N-methyl-norsalsolinol inhibited type B oxidase non-competitively to the substrate, and their Ki values were much higher than those to type A. Types of inhibition of type A monoamine oxidase depended on the enzyme sources. Inhibition of monoamine oxidase by 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines is discussed in relation to their chemical structures.