Electrophysiology automated

The potential of drugs to cause QT prolongation and the associated risk of cardio-toxicity remains an important issue in drug development. Although the advent of automated electrophysiological systems and other predinical screens has helped in early identification of hERG channel blockers, the outcome can be highly unsatisfactory. The process is wasteful and expensive and the development of potentially valuable compounds is halted. The wealth of information continually uncovered... 

Guo, L. and Guthrie, H. (2005) Automated electrophysiology in the predinical evaluation of drugs for potential QT prolongation. Journal of Pharmacological and Toxicological Methods, 52, 123-135. 

The inhibitory potencies of three of these molecules agreed with published values for murine Kv 3 (Table 4.1). The one exception was ShK that appeared to be 10-fold less potent than both published values and our own in-house values obtained by manual patch-clamp methods. It has been reported that ShK has a slow on-rate (t= 20 min) for block of Kv 3 (Middleton et al. 2003). This phenomenon may contribute to the reduced potency of ShK in our automated electrophysiology assay, because our protocol included a compound incubation time of only 5 to 10 min. Longer compound incubation times may improve the potency of ShK but would be associated with greater run-down in the K+ current amplitude. We also tested the A LI-selective blocker, dendrotoxin, and not surprisingly it did not inhibit the Kv. 3 current at concentrations up to 167 nM, which is well above its IC50 value for Kv 1.1 in our hands (17 pM data not shown). 

Wittel, A. et al. 2007. Assay development and primary screening of non-voltage-gated ion channels using IonWorks Quattro. Automated Electrophysiology Users Meeting, Baltimore, MD. 

Priest BT, Swensen AM, McManus OB. Automated electrophysiology in drug discovery. Curr. Pharm. Design 2007 13 2325-2337. 35. 

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