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Introduction Action potential repolarization is an important phenomenon in the heart, where it controls action potential duration (APD) and thus affects refractoriness and conduction of electrical impulses throughout the heart. [...], Activators of the slow delayed rectifier [K.sup.+] current ([I.sub.Ks]) have been suggested as promising tools for suppressing ventricular arrhythmias due to prolongation of repolarization. Recently, L-364,373 (R-L3) was nominated to activate [I.sub.Ks] in myocytes from several species; however, in some studies, it failed to activate [I.sub.Ks]. One later study suggested opposite modulating effects from the R-L3 enantiomers as a possible explanation for this discrepancy. Therefore, we analyzed the effect of the RL-3 enantiomers on [I.sub.Ks] in ventricular mammalian myocytes, by applying standard microelectrode and whole-cell patch- clamp techniques at 37°C. We synthesized 2 substances, ZS_1270B (right) and ZS_1271B (left), the 2 enantiomers of R- L3. In rabbit myocytes, ZS_1270B enhanced the [I.sub.Ks] tail current by approximately 30%, whereas ZS_1271B reduced [I.sub.Ks] tails by 45%. In guinea pig right ventricular preparations, ZS_1270B shortened [APD.sub.90] (action potential duration measured at 90% repolarization) by 12%, whereas ZS_1271B lengthened it by approximately 15%. We concluded that R-L3 enantiomers in the same concentration range indeed have opposite modulating effects on [I.sub.Ks], which may explain why the racemic drug R-L3 previously failed to activate [I.sub.Ks]. ZS_1270B is a potent [I.sub.Ks] activator, therefore, this substance is appropriate to test whether [I.sub.Ks] activators are ideal tools to suppress ventricular arrhythmias originating from prolongation of action potentials. Key words: L-364,373, slow delayed rectifier potassium current, [I.sub.Ks] activator, [I.sub.Ks] blocker, enantiomers, antiarrhythmic drugs. On a suggere que les activateurs du courant potassique rectifiant retarde lent ([I.sub.Ks]) soient des outils prometteurs pour supprimer les arythmies ventriculaires causees par la prolongation de la repolarisation. Recemment, le L-364,373 (R-L3) a ete identifie comme activateur du [I.sub.Ks] dans les myocytes de plusieurs especes ; toutefois, dans certaines etudes, il ne parvenait pas a activer le [I.sub.Ks]. Une etude ulterieure a suggere que les effets modulateurs opposes d'enantiomeres du R-L3 pourraient peut-etre expliquer cette divergence. Nous avons ainsi analyse l'effet d'enantiomeres de R-L3 sur le [I.sub.Ks] dans des myocytes ventriculaires de mammifere, en utilisant la technique standard de microelectrode et de patch clamp sur cellule entiere a 37°C. Nous avons synthetise deux substances, le ZS_1270B (droit) et le ZS_1271B (gauche), les deux enantiomeres du R-L3. Le ZS_1270B accroissait le courant [I.sub.Ks] de queue d'environ 30 % alors que le ZS_1271B reduisait les queues du [I.sub.Ks] de 45 %. Dans les preparations ventriculaires droites du cobaye, le ZS_1270B raccourcissait [l'APD.sub.90] de 12 % alors que le ZS_1271B l'allongeait inversement de 15 %. Nous avons conclu que les enantiomeres du R-L3 possedent effectivement des effets modulateurs opposes, ce qui peut expliquer pourquoi le melange racemique du medicament RL-3 ne parvenait pas a activer le [I.sub.Ks]. Le ZS_1270B est un puissant activateur du [I.sub.Ks] : consequemment, cette substance convient pour tester si les activateurs de [I.sub.Ks] sont effectivement des outils ideaux pour supprimer les arythmies ventriculaires emanant de la prolongations des potentiels d'action. [Traduit par la Redaction] Mots-cles: L-364,373, courant potassique rectifiant retarde lent, activateur du [I.sub.Ks], bloqueur du [I.sub.Ks], enantiomeres, medicaments anti-arythmiques.

A new library of pinane-based 1,4-amino alcohols was synthesised and utilised as chiral ligands in enantioselective diethylzinc addition to benzaldehyde. Aldol condensation of (+)-nopinone, derived from (–)-β-pinene, with 2-pyridinecarboxaldehyde gave the key intermediate α,β-unsaturated ketone, which was transformed in diastereoselective reduction, followed by hydrogenation, resulting in 1,4-amino alcohols. On the other hand, epoxidation of the α,β-unsaturated ketone, followed by reduction and then hydrogenation of the pyridine ring, afforded a mixture of 4-amino-2,3-epoxy-1-ols. Stereoselective hydride reduction of the epoxy ketone and subsequent condensation of the resulting products with substituted benzyl bromides provided quaternary ammonium salts, which were subjected to hydride reduction and then hydrogenation, affording 4-amino-2,3-epoxy-1-ol derivatives containing an N -benzylpiperidine moiety. The inhibition of nucleophile-initiated opening of the oxirane ring was interpreted by a systematic series- of comparative Hartree–Fock modelling study using the 6-31+G(d,p) basis set. The antiproliferative activities of 4-amino-2,3-epoxy--1-ol derivatives were examined, and structure–activity relationships were studied from the aspects of the stereochemistry of the oxirane ring, saturation, and substituent effects on the piperidine ring system. [ABSTRACT FROM AUTHOR]