Stereoselective Interactions Between Local Anesthetics and Cardiac K+ Channels

Ionic channels are membrane proteins that can be blocked by many different types of drugs such as local anesthetics, antiarrhythmics, etc. Therefore, they are considered drug targets, whose topology, at the ion channel level, has been analyzed by studying the interactions of specific ion channel blockers and site-directed mutant ion channels. Stereoselective interactions are especially interesting because they can reveal three-dimensional relationships between drugs and channels with otherwise identical biophysical and physicochemical properties. Furthermore, stereoselectivity suggests direct and specific receptor-mediated action, and identification of such stereospecific interactions may have important clinical consequences. However, ≈25% of drugs used in clinical practice are racemic mixtures, the individual enantiomers of which frequently differ in both their pharmacodynamic and pharmacokinetic profile. Furthermore, these different effects induced by one of the enantiomers of a racemic drug may contribute to the undesired effects that can be similar or different to the pharmacological effect of the racemic drug. In other cases, the enantiomers on the molecular target are opposite. In this review, we focus on the stereoselective effects of bupivacaine on different Kv channels. Bupivacaine stereoselectively blocks Kv1.5 and Kv11.1 channels, whereas non-stereoselectively it blocks Kv2.1 and Kv4.3 channels.