Pharmacological and electrophysiological characterization of AZSMO-23, an activator of the hERG K+ channel.

Background and Purpose We aimed to characterize the pharmacology and electrophysiology of N-[3-(1 H-benzimidazol-2-yl)-4-chloro-phenyl]pyridine-3-carboxamide ( AZSMO-23), an activator of the human ether-a-go-go-related gene ( hERG)-encoded K+ channel ( Kv11.1). Experimental Approach Automated electrophysiology was used to study the pharmacology of AZSMO-23 on wild-type ( WT), Y652 A, F656 T or G628 C/ S631 C hERG, and on other cardiac ion channels. Its mechanism of action was characterized with conventional electrophysiology. Key Results AZSMO-23 activated WT hERG pre-pulse and tail current with EC50 values of 28.6 and 11.2 μM respectively. At 100 μM, pre-pulse current at +40 mV was increased by 952 ± 41% and tail current at −30 mV by 238 ± 13% compared with vehicle values. The primary mechanism for this effect was a 74.5 mV depolarizing shift in the voltage dependence of inactivation, without any shift in the voltage dependence of activation. Structure-activity relationships for this effect were remarkably subtle, with close analogues of AZSMO-23 acting as hERG inhibitors. AZSMO-23 blocked the mutant channel, hERG Y652 A, but against another mutant channel, hERG F656 T, its activator activity was enhanced. It inhibited activity of the G628 C/ S631 C non-inactivating hERG mutant channel. AZSMO-23 was not hERG selective, as it blocked hKv4.3- hKChIP2.2, hCav3.2 and hKv1.5 and activated hCav1.2/β2/α2δ channels. Conclusion and Implications The activity of AZSMO-23 and those of its close analogues suggest these compounds may be of value to elucidate the mechanism of type 2 hERG activators to better understand the pharmacology of this area from both a safety perspective and in relation to treatment of congenital long QT syndrome. [ABSTRACT FROM AUTHOR]