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1. CPU86017 is an effective anti-arrhythmic agent of the Class III complex that has two chiral centres, 7N and 13aC. As a promising anti-arrhythmic agent, the blockade on I(Kr), I(Ks) and calcium influx may be modulated to be mild, moderate and potent, with less a-adrenoceptor blockade. In order to improve activity at ion channels, four stereoisomers, namely SS ((+)-7S,13aS-CPU86017), SR ((-)-7S,13aR-CPU86017), RR ((-)-7R,13aR-CPU86017) and RS ((+)-7R,13aS-CPU86017), have been separated. In the present study, the effects of these four isomers on I(Kr) and I(Ks), calcium channels and a-adrenoceptors were compared with the effects of the racemate CPU86017. 2. In the present study, I(Kr) and I(Ks) were measured as tail currents (I(Kr.tail) and I(Ks.tail), respectively) using the whole-cell patch-clamp technique. Antagonism of receptor-operated calcium channels and voltage-dependent calcium channels (VDC) in vascular smooth muscle by CPU86017 and the four isomers were tested as suppression of phenylephrine- or KCl-induced contractions of aortic rings, respectively. 3. For I(Kr.tail) inhibition, the IC(50) of SS, SR, RR, RS and CPU86017 was 2.86 +/- 1.20, 39.4 +/- 8.5, 3.48 +/- 0.80, 7.65 +/- 1.50 and 12.5 +/- 7.8 x 10(-9) mol/L, respectively; for I(Ks.tail) inhibition IC(50) values were 16.9 +/- 4.0, 20.0 +/- 2.1, 99.1 +/- 5.9, 160 +/- 81 and 65.0 +/- 4.7 x 10(-9) mol/L, respectively. The SR isomer showed balanced blockade of I(Kr) and I(Ks) that was associated with a loss of a-adrenoceptor antagonism but enhanced VDC blockade. 4. Configuration of 13aC critically determines I(Kr) blockade and the Ca(2+) antagonism of the isomers of CPU86017. The SR isomer exhibits mild blockade of I(Kr), moderately enhanced blockade of I(Ks) and Ca(2+) influx and less a-adrenoceptor antagonism compared with the racemate and may be promising as an anti-arrhythmic.
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