22988-16-5Relevant articles and documents
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 (2000)
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.
Light-Induced Alkylation of (Hetero)aromatic Nitriles in a Transition-Metal-Free C-C-Bond Metathesis
Lipp, Benjamin,Lipp, Alexander,Detert, Heiner,Opatz, Till
, p. 2054 - 2057 (2017/04/27)
A light-induced C-C-σ-bond metathesis was achieved through transition-metal-free activation of an unstrained C(sp3)-C(sp3)-σ-bond in 1-benzyl-1,2,3,4-tetrahydroisoquinolines. A photoredox-mediated single-electron oxidation of these precursor amines yield radical cations which undergo a homolytic cleavage of a C(sp3)-C(sp3)-σ-bond rather than the well-known α-C-H-scission. The resulting carbon-centered radicals are used in the ipso-substitution of (hetero)aromatic nitriles proceeding through another single-electron transfer-mediated C-C-bond cleavage and formation.
Total Synthesis of Tetrahydroisoquinoline-Based Bioactive Natural Products Laudanosine, Romneine, Glaucine, Dicentrine, and Their Unnatural Analogues Isolaudanosine and Isoromneine
Jangir, Ravi,Argade, Narshinha P.
, p. 1655 - 1663 (2017/03/21)
Starting from suitably substituted homophthalic acids, total synthesis of titled alkaloids have been demonstrated in very good yields. The obtained natural products laudanosine and romneine were utilized to accomplish synthesis of two isoquinoline-based alkaloids glaucine and dicentrine. Base-induced selective generation of two different types of benzylic carbanions, their coupling reactions with 3,4-dimethoxybenzyl mesylate, and the regioselective iodination followed by intramolecular aryl-aryl coupling reactions to form the fused biaryl systems were the strategic steps.
Synthesis and biological evaluation of N-methyl-laudanosine iodide analogues as potential SK channel blockers
Graulich,Mercier,Scuvee-Moreau,Seutin,Liegeois
, p. 1201 - 1209 (2007/10/03)
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
