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- W1973245869 abstract "The potential for stereoselectivity of hERG K+ channel inhibition by drugs that exist as racemic mixtures is recognised; stereoselectivity has been established for some compounds (reviewed in (1)). Both the class Ia antiarrhythmic drug disopyramide (DISO) and the serotonin-selective reuptake inhibitor citalopram exist as racemic mixtures. Both have been associated with cases of drug-induced QT prolongation, with its attendant risk of torsades de pointes (TdP). Prior work has established that both compounds inhibit hERG current (IhERG) significantly at low micromolar concentrations (eg 2,3). In this study, we have investigated the potential for stereoselective hERG current (IhERG) inhibition by these drugs.Whole-cell patch-clamp measurements of IhERG were made at 37°C from hERG-expressing HEK 293 cells. All observations reported here are from at least 5 replicates. For citalopram, action potential voltage-clamp experiments were performed on racemic citalopram and the S(+) enantiomer (escitalopram). Application of 3μM citalopram inhibited maximal IhERG during the repolarisation phase of the AP by 69.6±3.6%, whilst escitalopram blocked the current by 63.4±7.1% (p>0.05, student t test). On the other hand, with a conventional screening protocol (S+) DISO was found to block IhERG ∼3 -fold more potently than did (R-) DISO (IC50 values of 3.9±0.6 μM and 12.9±1.4 μM respectively with normal (4mM) [K+]e). With high (94 mM) [K+]e, the IC50 values for (S+) and (R-) DISO were 16.9 ±3.0 μM and 61.1±7.4 μM respectively.Our data provide evidence that disopyramide exhibits stereoselective inhibition of IhERG. Our initial findings with citalopram are suggestive of a lack of notable stereoselectivity for that compound, though this needs further investigation.Funded by the British Heart Foundation(1) Grilo LS, et al, Front Pharmacol, 2010;1:137.(2) Ashok AP,et al, BBSRC, 2001, 280:1243-1250.(3) Witchel HJ, et al, FEBS Lett 2002;512:59-66." @default.
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- W1973245869 date "2014-01-01" @default.
- W1973245869 modified "2023-09-29" @default.
- W1973245869 title "Inverstigating Stereoselectivity of Pharmacological Inhibition of Herg Channels" @default.
- W1973245869 doi "https://doi.org/10.1016/j.bpj.2013.11.809" @default.
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