Activation of KCNQ5 channels stably expressed in HEK293 cells by BMS-204352.
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.
Dupuis
Delphine S
DS
Department of Medical Physiology, University of Copenhagen, The Panum Institute, 3 Blegdamsvej, DK 2200 Copenhagen N, Denmark. delphine@mfi.ku.dk
Schrøder
Rikke L
RL
Jespersen
Thomas
T
Christensen
Jeppe K
JK
Christophersen
Palle
P
Jensen
Bo S
BS
Olesen
Søren P
SP
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
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