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 muM. At 10 muM, 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 [Schrphider ct 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 muM) did not significantly shift the KCNQ5 activation curves (threshold and potential for half-activation, V-1/2), 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 Mcurrent blockers, linopirdine (DuP 996; 3,3 -bis (4-pyridinylmethyl)-l-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 proper-ties of the compound on the KCNQ5 channel seems to be different from what has been obtained on the other KCNQ channels. (C) 2002 Elsevier Science B.V. All rights reserved.