50370-93-9Relevant academic research and scientific papers
Synthesis and biological evaluation of N-methyl-laudanosine iodide analogues as potential SK channel blockers
Graulich,Mercier,Scuvee-Moreau,Seutin,Liegeois
, p. 1201 - 1209 (2005)
Neuronal action potentials are followed by an afterhyperpolarisation (AHP), which is mediated by small conductance Ca2+-activated K+ channels (SK channels or KCa2 channels). This AHP plays an important role in regulating neuronal act
Dopamine transporter and catechol-O-methyltransferase activities are required for the toxicity of 1-(3′,4′-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline
Kawai, Hiroshi,Kotake, Yaichiro,Ohta, Shigeru
, p. 1294 - 1301 (2007/10/03)
1-(3′,4′-Dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline [3′,4′DHBnTIQ (1)] is an endogenous parkinsonism-inducing substance. It is taken up into dopaminergic neurons via the dopamine transporter, inhibits mitochondrial respiration, and induces parkinsonism in mice. We synthesized four derivatives [aromatized, N-methylated, N-methyl-aromatized, and O-methylated (2-5, respectively)] and studied the cellular uptake and cytotoxicity of 1-5, as well as the metabolism of 1. All except the O-methyl derivative (5) were specifically taken up by the dopamine transporter, but 1 was taken up most efficiently. Relative to 1, oxidation reduced νmax, N-methylation markedly increased Km, and O-methylation eliminated the uptake activity. The cytotoxicity of 1-5 was examined in a mesencephalic cell primary culture. Compound 1 reduced cell viability by nearly 80% at 100 μM, but the other compounds had little or no effect on cell viability. In vivo and in vitro studies revealed that 1 was O-methylated by soluble catechol-O-methyltransferase (COMT). Aromatization and N-methylation of 1 were not observed. We found that dopamine transporter inhibitors and a COMT inhibitor each blocked the cytotoxicity of 1, indicating that uptake and O-methylation are both necessary for neurotoxicity. Thus, we consider that 1 is taken up into dopaminergic neurons via the dopamine transporter and then converted by COMT to 5, which has cytotoxic and parkinsonism-inducing activities.
