title: Activation of KCNQ5 channels stably expressed in HEK293 cells by BMS-204352.
abstract: The novel anti-ischemic compound, BMS-204352 ((3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one)), strongly activates the voltage-gated K+ channel KCNQ5 in a concentration-dependent manner with an EC50 of 2.4 microM. At 10 microM, BMS-204352 increased the steady state current at -30 mV by 12-fold, in contrast to the 2-fold increase observed for the other KCNQ channels [Schrøder et al., 2001]. Retigabine ((D-23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) induced a smaller, yet qualitatively similar effect on KCNQ5. Furthermore, BMS-204352 (10 microM) did not significantly shift the KCNQ5 activation curves (threshold and potential for half-activation, V1/2), as observed for the other KCNQ channels. In the presence of BMS-204352, the activation and deactivation kinetics of the KCNQ5 currents were slowed as the slow activation time constant increased up to 10-fold. The M-current blockers, linopirdine (DuP 996; 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one) and XE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone), inhibited the activation of the KCNQ5 channel induced by the BMS-204352. Thus, BMS-204352 appears to be an efficacious KCNQ channels activator, and the pharmacological properties of the compound on the KCNQ5 channel seems to be different from what has been obtained on the other KCNQ channels.
authors.affiliation: Department of Medical Physiology, University of Copenhagen, The Panum Institute, 3 Blegdamsvej, DK 2200 Copenhagen N, Denmark. delphine@mfi.ku.dk
authors.forename: Delphine S
authors.initials: DS
authors.lastname: Dupuis
authors.forename: Rikke L
authors.initials: RL
authors.lastname: Schrøder
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
authors.forename: Jeppe K
authors.initials: JK
authors.lastname: Christensen
authors.forename: Palle
authors.initials: P
authors.lastname: Christophersen
authors.forename: Bo S
authors.initials: BS
authors.lastname: Jensen
authors.forename: Søren P
authors.initials: SP
authors.lastname: Olesen
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051656:KCNQ Potassium Channels; D008564:Membrane Potentials / Q000187:drug effects; D010655:Phenylenediamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines / Q000494:pharmacology
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; C424388:BMS204352; D002219:Carbamates; D007211:Indoles; D051656:KCNQ Potassium Channels; C412231:KCNQ5 protein, human; D010655:Phenylenediamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; C101866:ezogabine; C061017:linopirdine