Stereoselective effects of the enantiomers of a new local anaesthetic, IQB-9302, on a human cardiac potassium channel (Kv1.5)

1 The N-substituent of IQB-9302 has the same number of carbons as bupivacai ne, but it exhibits a different spatial localization (n-butyl Is cyclopropy lmethyl). Thus, the study of the effects of IQB-9302 enantiomers on hKv1.5 channels will lead to a better knowledge of the determinants of stereoselec tive block. 2 The effects of the IQB-9302 enantiomers were studied on hKv1.5 channels s tably expressed in Ltk(-) cells using the whole-cell configuration of the p atch-clamp technique. Drug molecular modelling was performed using Hyperche m software. 3 Block induced by IQB-9302 was stereoselective with the R(+) enantiomer be ing 3.2-fold more potent than the S(-) one (K-D of 17.8+/-0.5 muM vs 58.6+/ -4.0 muM). 4 S(-)- and R(+)IQB-9302 induced-block was time- and voltage-dependent cons istent with an electrical distance from the cytoplasmic side of 0.173+/-0.0 22 (n=12) and 0.181+/-0.018 (n=10), respectively. 5 Potency of block of pipecoloxylidide local anaesthetics was linearly rela ted to the length between the cationic tertiary amine and the end of the su bstituent. 6 Molecular modelling shows that only when S(-) and R(+)enantiomers are sup erimposed by their aromatic ring, their N-substituents are in opposite dire ctions, which can explain the stereospecific block induced by bupivacaine a nd IQB-9302 with hKv1.5 channels. 7 These results suggest that: (a) IQB-9302 enantiomers block the open state of hKv1.5 channels, and (b) the length of the N-substituent in these local anaesthetics and not its volume determines the potency and degree of their stereoselective hKv1.5 channel block.