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-(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.

Read more here: Mannikko R, Bridgland-Taylor MH, Pye H, Swallow S, Abi-Gerges N, Morton MJ, Pollard CE. (2015) Pharmacological and electrophysiological characterization of AZSMO-23, an activator of the hERG K(+) channel. Br J Pharmacol. Jun;172(12):3112-25.

By |2018-06-20T16:06:22+00:00June 20th, 2015|Ion Channels, Publications|Comments Off on Pharmacological and electrophysiological characterization of AZSMO-23, an activator of the hERG K(+) channel

About the Author:

Dr Michael Morton, PhD, Director and Cofounder, ApconiX, UK, an integrated toxicology and ion channel company that brings together a team of world-renowned nonclinical safety experts with over 400 years of drug discovery and development experience. Mike graduated from the University of Wolverhampton with a degree in Biomedical Sciences and then aspiration to work in hospital pathology. Having finished his Sandwich placement in Clinical Biochemistry at Sandwell Hospital and Mike subsequently gained a MSc in Clinical Biochemistry from the University of Manchester and carried out research into porphyrin metabolism. Moving to the University of Leeds, Mike completed his PhD in Pharmacology at researching adenosine receptor expression in the rat kidney . Mike was introduced to ion channels as a Post-Doc at Leeds and Yale University, patching with the likes of Fred Sigworth and Steve Hebert, then joined the Global Ion Channel Initiative at AstraZeneca. Mike worked at AstraZeneca for eight years before founding ApconiX with Professor Ruth Roberts and Dr Richard Knight. Mike has a serious passion for ion channels. And he’s very good at them . He is a serious scientist (with a serious sense of humour) who wants to make sure that every customer understands the consequences of the results he obtains and works with his colleagues to ensure a better decision is made on drug safety.