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CHIRAL SEPARATION OF RACEMATE CPU86017, AN ANTI‐ARRHYTHMIC AGENT, PRODUCES STEREOISOMERS POSSESSING FAVOURABLE ION CHANNEL BLOCKADE AND LESS α‐ADRENOCEPTOR ANTAGONISM
Author(s) -
Li Na,
Yang Lin,
Dai DeZai,
Wang QiuJuan,
Dai Yin
Publication year - 2007
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2007.04854.x
Subject(s) - chemistry , antagonism , phenylephrine , blockade , stereochemistry , voltage dependent calcium channel , ic50 , calcium channel , enantiomer , calcium , patch clamp , ion channel , pharmacology , receptor , medicine , in vitro , biochemistry , biology , organic chemistry , blood pressure
SUMMARY1 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 ¥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 ¥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.