title: [3H]linopirdine binding to rat brain membranes is not relevant for M-channel interaction.
abstract: Linopirdine was developed as a cognitive enhancing molecule and demonstrated to specifically block the potassium current generated by the brain specific KCNQ2-KCNQ3 proteins (M-channel). In this study we investigated the relevance of [(3)H]linopirdine binding in rat brain extracts to the interaction with the M-channel proteins. Our results confirm the presence of a high affinity site for [(3)H]linopirdine in rat brain tissues (KD = 10 nM) but we also identified a high affinity binding site for [(3)H]linopirdine in rat liver tissues (KD = 9 nM). Competition experiments showed that [(3)H]linopirdine is displaced by unlabelled linopirdine with comparable affinities from its binding sites on rat brain and rat liver membranes. [(3)H]linopirdine was completely displaced by a set of cytochrome P450 (CYP450) ligands suggesting that [(3)H]linopirdine binding to rat brain and liver membranes is linked to CYP450 interaction. The testing of CYP450 ligands on the M-channel activity, using a Rb(+) efflux assay on cells expressing the KCNQ2-KCNQ3 proteins, demonstrated that [(3)H]linopirdine binding results cannot be correlated to M-channel inhibition. The results obtained in this study demonstrate that [(3)H]linopirdine binding to rat brain and rat liver membranes is representative for CYP450 interaction and not relevant for the binding to the M-channel proteins.
authors: Deparment of in vitro Pharmacology, UCB SA, CNS Preclinical Research, chemin du Foriest R4, 1420 Braine l' Alleud, Belgium. christian.wolff@ucb-group.com
authors: Christian
authors: C
authors: Wolff
authors: Michel
authors: M
authors: Gillard
authors: Bruno
authors: B
authors: Fuks
authors: Pierre
authors: P
authors: Chatelain
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000378:metabolism* / Q000494:pharmacology; D051659:KCNQ3 Potassium Channel; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008825:Miconazole / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012413:Rubidium / Q000378:metabolism; D014316:Tritium
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D002712:Chlorides; D007211:Indoles; D051659:KCNQ3 Potassium Channel; C496918:Kcnq3 protein, rat; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D014316:Tritium; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D011738:Pyrilamine; C061017:linopirdine; D011802:Quinidine; D012413:Rubidium; C032710:rubidium chloride; D007654:Ketoconazole