title: Stereoselective effects of the enantiomers of a new local anaesthetic, IQB-9302, on a human cardiac potassium channel (Kv1.5).
abstract: 1. The N-substituent of IQB-9302 has the same number of carbons as bupivacaine, but it exhibits a different spatial localization (n-butyl vs cyclopropylmethyl). Thus, the study of the effects of IQB-9302 enantiomers on hKv1.5 channels will lead to a better knowledge of the determinants of stereoselective block. 2. The effects of the IQB-9302 enantiomers were studied on hKv1.5 channels stably expressed in LTK:(-) cells using the whole-cell configuration of the patch-clamp technique. Drug molecular modelling was performed using Hyperchem software. 3. Block induced by IQB-9302 was stereoselective with the R(+) enantiomer being 3.2-fold more potent than the S(-) one (K(D) of 17.8+/-0.5 microM vs 58.6+/-4.0 microM). 4. S(-)- and R(+)IQB-9302 induced-block was time- and voltage-dependent consistent with an electrical distance from the cytoplasmic side of 0.173+/-0.022 (n=12) and 0.181+/-0.018 (n=10), respectively. 5. Potency of block of pipecoloxylidide local anaesthetics was linearly related to the length between the cationic tertiary amine and the end of the substituent. 6. Molecular modelling shows that only when S(-) and R(+) enantiomers are superimposed by their aromatic ring, their N-substituents are in opposite directions, which can explain the stereospecific block induced by bupivacaine and 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.
authors.affiliation: Institute of Pharmacology and Toxicology, CSIC/UCM. School of Medicine, Universidad Complutense. 28040 Madrid, Spain. carmenva@eucmax.sim.ucm.es
authors.forename: T
authors.initials: T
authors.lastname: González
authors.forename: M
authors.initials: M
authors.lastname: Longobardo
authors.forename: R
authors.initials: R
authors.lastname: Caballero
authors.forename: E
authors.initials: E
authors.lastname: Delpón
authors.forename: J V
authors.initials: JV
authors.lastname: Sinisterra
authors.forename: J
authors.initials: J
authors.lastname: Tamargo
authors.forename: C
authors.initials: C
authors.lastname: Valenzuela
mesh_terms: D000465:Algorithms; D000577:Amides / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology*; D002045:Bupivacaine / Q000494:pharmacology; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects*; D006801:Humans; D051666:Kv1.5 Potassium Channel; D008564:Membrane Potentials / Q000502:physiology; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D024642:Potassium Channels, Voltage-Gated; D000077212:Ropivacaine; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D000577:Amides; D000779:Anesthetics, Local; C418003:IQB 9302; C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; D010880:Piperidines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D000077212:Ropivacaine; D002045:Bupivacaine