[en] Starting from the scaffold of N-methyllaudanosine and N-methylnoscapine, which are known small conductance Ca2+-activated K+ channel blockers, original bis-isoquinolinium derivatives were synthezised and evaluated using binding studies, electrophysiology, and molecular modeling. These quaternary compounds are powerful blockers, and the most active ones have 10 times more affinity for the channels than dequalinium. The unsubstituted compounds possess a weaker affinity than the analogues having a 6,7-dimethoxy- or a 6,7,8-trimethoxy substitution. The length of the linker has no influence in the alkane derivatives. In relation to the xylene derivatives, the affinities are higher for the ortho and meta isomers. These results are well corroborated by a molecular modeling study. Finally, the most effective compounds have been tested in electrophysiological experiments on midbrain dopaminergic neurons and demonstrate the blocking potential of the apamin-sensitive after-hyperpolarization.
Dilly, Sébastien ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Pharmacologie
Farce, Amaury
Scuvée-Moreau, Jacqueline ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Pharmacologie - Département des sciences biomédicales et précliniques
Koehler, M.; Hirschberg, B.; Bond, C. T.; Kinzie, J. M.; Marrion, N. V.; Maylie, J.; Adelman, J. P. Small-conductance, calcium-activated potassium channels from mammalian brain. Science 1996, 273, 1709-1714.
Stocker, M.; Krause, M.; Pedarzani, P. An apamin-sensitive Ca 2+-activated K+ current in hippocampal pyramidal neurons. Proc. Natl. Acad. Sci. USA. 1999, 96, 4662-4667.
Stocker, M.; Pedarzani, P. Differential distribution of three Ca 2+-activated K+ channel subunits, SK1, SK2 and SK3, in the adult rat central nervous system. Mol. Cell. Neurosci. 2000, 15, 476-493.
Messier, C.; Mourre, C.; Bontempi, B.; Sif, J.; Lazdunski, M.; Destrade, C. Effect of apamin, a toxin that inhibits calcium-dependent potassium channels, on learning and memory processes. Brain Res. 1991, 551, 322-326.
Deschaux, O.; Bizot, J. C.; Goyffon, M. Apamin improves learning in an object recognition task in rats. Neurosci. Lett. 1997, 222, 159-162.
Ikonen, S.; Riekkinen, P., Jr. Effect of apamin on memory processing of hippocampal-lesioned mice. Eur. J. Pharmacol. 1999, 382, 151-156.
Van der Staay, F. J.; Fanelli, R. J.; Blokland, A.; Schmidt, B. H. Behavioral effects of apamin, a selective inhibitor of the SKCa channel, in mice and rats. Neurosci. Biobehav. Rev. 1999, 23, 1087-1110.
Fournier, C.; Kourrich, S.; Soumireu-Mourat, B.; Mourre, C. Apamin improves reference memory but not procedural memory in rats by blocking small conductance Ca2+-activated K+ channels in an olfactory discrimination task. Behav. Brain Res. 2001, 121, 81-93.
Pedarzani, P.; Mosbacher, J.; Rivard, A.; Cingolani, L. A.; Oliver, D.; Stocker, M.; Adelman, J. P.; Fakler, B. Control of electrical activity in central neurons by modulating the gating of small conductance Ca 2+-activated K+ channels. J. Biol. Chem. 2001, 276, 9762-9769.
Steketee, J. D.; Kalivas, P. W. Effect of microinjections of apamin into the A10 dopamine region of rats: a behavioural and neurochemical analysis. J. Pharmacol. Exp. Ther. 1990, 254, 711-719.
Shepard, P. D.; Bunney, B. S. Repetitive firing properties of putative dopamine-containing neurons in vitro: regulation by an apamin-sensitive Ca 2+-activated K+ conductance. Exp. Brain Res. 1991, 86, 141-150.
Seutin, V.; Johnson, S. V.; North, R. A. Apamin increases NMDA-induced burst firing of rat mesencephalic dopamine neurons. Brain Res. 1993, 630, 341-344.
Vincent, J. P.; Schweitz, H.; Lazdunski, M. Structure-function relationships and site of action of apamin, a neurotoxic polypeptide of bee venom with an action on the central nervous system. Biochemistry 1975, 14, 2521-2525.
Campos Rosa, J.; Galanakis, D.; Piergentili, A.; Bhandari, K.; Ganellin, C. R.; Dunn, P. M.; Jenkinson, D. H. Synthesis, molecular modelling, and pharmacological testing of bis-quinolinium cyclophanes: potent, non-peptidic blockers of the apamin-sensitive Ca2+-activated K+ channel. J. Med. Chem. 2000, 43, 420-431.
Scuvée-Moreau, J.; Liégeois, J.-F.; Massotte, L.; Seutin, V. Methyl-laudanosine: a new pharmacological tool to investigate the function of small-conductance Ca2+-activated K+ channels. J. Pharmacol. Exp. Ther. 2002, 302, 1176-1183.
Scuvée-Moreau, J.; Boland, A.; Graulich, A.; Van Overmeire, L.; D'hoedt, D.; Graulich-Lorge, F.; Thomas, E.; Abras, A.; Stocker, M.; Liégeois, J.-F.; Seutin, V. Electrophysiological characterization of the SK channel blockers methyl-laudanosine and methyl-noscapine in cell lines and rat brain slices. Br. J. Pharmacol. 2004, 143, 753-764.
Birch, A. J.; Jackson, A. H.; Shannon, V. R. A new modification of the Pomeranz-Fritsch isoquinoline synthesis. J. Chem. Soc., Perkin Trans. 1. 1974, 2185-2190.
Popp, F. D. Developments in the chemistry of Reissert compounds (1968-1978). Adv. Heterocycl. Chem. 1979, 24, 187-214.
Ruchirawat, S.; Phadungkul, N.; Chuankamnerdkarn, M.; Thebtaranonth, C. A versatile synthesis of Reissert compounds. Heterocycles 1977, 6, 43-46.
Popp, F.; Klinowski, C.; Piccirilli, R.; Purcell, D.; Watts, R. Reissert compound studies. XXIII. Reaction of the anion with some difunctional compounds. J. Heterocycl. Chem. 1971, 8, 313-315.
Dilly, S.; Graulich, A.; Farce, A.; Seutin, V.; Liégeois, J.-F.; Chavatte, P. Identification of a pharmacophore of SKCa channel blockers. J. Enzyme Inhib. Med. Chem. 2005, 6, 517-523.
Galanakis, D.; Davis, C.; Del Rey Herrero, B.; Ganellin, R.; Dunn, P.; Jenkinson, D. Synthesis and structure-activity relationships of dequalinium analogues as K+ channel blockers. Investigations on the role of the charged heterocycle. J. Med. Chem. 1995, 38, 595-606.
Graulich, A.; Mercier, F.; Scuvée-Moreau, J.; Seutin, V.; Liégeois, J.-F. Synthesis and biological evaluation of N-methyl-laudanosine iodide analogues as potential SK channel blockers. Bioorg. Med. Chem. 2005, 13, 1201-1209.
Graulich, A.; Scuvée-Moreau, J.; Alleva, L.; Lamy, C.; Waroux, O.; Seutin, V.; Liégeois, J.-F. Synthesis and radioligand binding studies of methoxylated-1,2,3,4-tetrahydroisoquinolinium derivatives as ligands of the apamine-sensitive Ca2+-activated K+ channels. J. Med. Chem. 2006, 49, 7208-7214.
Graulich, A.; Scuvée-Moreau, J.; Seutin, V.; Liégeois, J.-F. Synthesis and radioligand binding studies of C-5 and C-8-substituted 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums as SK channel blockers related to N-methyl-laudanosine and N-methylnoscapine. J. Med. Chem. 2005, 48, 4972-4982.
Galanakis, D.; Ganellin, C. R.; Chen, J.-Q.; Gunasekera, D.; Dunn, P. M. Bis-quinolinium cyclophanes: toward a pharmacophore model for the blockade of apamin-sensitive SKCa channels in sympathetic neurons. Bioorg. Med. Chem. 2004, 14, 4231-4235.
Uff, B.; Kershaw, J.; Neumeyer, J. Alkylation of isoquinolines via 2-benzoyl-1,2-dihydroisoquinaldonitriles: 1-benzylisoquinoline. Org. Synth. 1977, 56, 19-25.
Hartree, E. F. Determination of protein: a modification of the Lowry method that gives a linear photometric response. Anal. Biochem. 1972, 48, 422-427.
Goldstein, S.; Neuwels, M.; Moureau, F.; Berkmans, D.; Lassoie, M. A.; Differding, E.; Houssin, R.; Hénichart, J. P. Bioactive conformations of peptides and mimetics as milestones in drug design: investigation of NK 1 receptor antagonists. Lett. Pept. Sci. 1995, 2, 125-134.
Crippen G. M. Distance Geometry and Conformational Calculations; Research Studies Press (Wiley): New York, 1981.
Clark, M.; Cramer, R. D., III; Van Opdenbosch, N. Validation of the general purpose Tripos 5.2 force field. J. Comput. Chem. 1989, 10, 982-1012.