1,2,3,4-Tetrahydro-2-methyl-4,6,7-isoquinolinetriol inhibits tyrosine hydroxylase activity in rat striatal synaptosomes.
1,2,3,4-tetrahydro-2-methyl-4,6,7-isoquinolinetriol (TMIQ), a tetrahydroisoquinoline derivative of adrenaline, was tested for potency as an analog of the dopamine depleting agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in assays of tyrosine hydroxylase (TH) activity in the striatal synaptosome preparation. TMIQ inhibited TH activity with an IC50 (4 x 10(-6)M) similar to that found for MPTP (IC50 1 x 10(-6)M). TH inhibitions produced by IC50 concentrations of TMIQ were reversed by monoamine oxidase (MAO)-A or MAO-B inhibitors (clorgyline or deprenyl), or the dopamine reuptake blocker nomifensine, or excess cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin. TMIQ did not appear to act at the presynaptic D2 sulpiride sensitive autoreceptor for dopamine synthesis modulation. These in vitro data are consistent with earlier findings that TMIQ acts as a dopamine depleting agent, and with the possibility that TMIQ may have a degree of MPTP-like activity in vivo.
Department of Anatomy, School of Medical Sciences, University of Bristol, United Kingdom.
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D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003010:Clorgyline / Q000494:pharmacology; D003342:Corpus Striatum / Q000201:enzymology* / Q000648:ultrastructure; D004298:Dopamine / Q000096:biosynthesis; D007546:Isoquinolines / Q000494:pharmacology*; D008995:Monoamine Oxidase / Q000502:physiology*; D009243:NAD / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D009627:Nomifensine / Q000494:pharmacology; D010300:Parkinson Disease; D051381:Rats; D012642:Selegiline / Q000494:pharmacology; D013469:Sulpiride / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects* / Q000201:enzymology; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors*
D007546:Isoquinolines; D009419:Nerve Tissue Proteins; D009243:NAD; D009627:Nomifensine; D001708:Biopterins; D012642:Selegiline; D013469:Sulpiride; C084360:1,2,3,4-tetrahydro-2-methyl-4,6,7-isoquinolinetriol; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; C003402:sapropterin; D003010:Clorgyline; D004298:Dopamine