Background and Purpose
We aimed to characterize the pharmacology and electrophysiology of N‐[3‐(1H‐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), Y652A, F656T or G628C/S631C 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 Y652A, but against another mutant channel, hERG F656T, its activator activity was enhanced. It inhibited activity of the G628C/S631C 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.