Efficient characterization of use-dependent ion channel blockers by real-time monitoring of channel state

Assay and Drug Development Technologies
Huimin TaoAndrea Ghetti

Abstract

Ion channels are important therapeutic targets for the treatment of a variety of conditions. Among ion channel blocking agents, use-dependent inhibitors can be especially effective therapeutic agents. Use dependence allows the selective inhibition of hyperactive neurons or tachycardiac myocytes, while minimizing effects on cells with normal activity. For voltage-gated channels, the use-dependent compounds typically bind to and inhibit a particular kinetic state that is induced by specific voltage changes. Drug discovery programs that focus on this class of drugs need to rank the use dependence of the compounds. A meaningful comparison among different molecules requires voltage clamp-based assays with continuous voltage control and compensation for or elimination of electrode drift-related effects. A method was developed based on automated electrophysiology in which voltage and frequency dependence of voltage-gated ion channel blockers can be compared using a protocol in which voltage error is compensated for in real time.

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Citations

Dec 17, 2009·Expert Opinion on Investigational Drugs·Jeffrey J Clare
Nov 7, 2015·Nature Reviews. Drug Discovery·Gerald W Zamponi
Jul 6, 2010·Journal of Pharmacological and Toxicological Methods·Jacob R PennimanJohn P Imredy

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