Different pharmacological properties of the optical isomers of MN9202, a novel 1,4‐dihydropyridine Ca2+ channel modulator,in rat ventricular myocytes

1. We have shown previously that 1,4‐dihydro‐2,6‐dimethyl‐4‐(3‐nitrophenyl)‐3,5‐pyridinedicarboxylic acid pentyl methyl ester (MN9202), a new 1,4‐dihydropyridine Ca²⁺ channel modulator, has significant hypotensive effects and favourable pharmacokinetic characteristics. As a chiral molecule, MN9202 has two optical isomers. The aim of the present study was to evaluate the pharmacological properties of the two enantiomers. 2. The two enantiomers, S‐(?)‐ and R‐(+)‐MN9202, were obtained by HPLC. At 1 μmol/L, both racemic MN9202 and S‐(?)‐MN9202 decreased the contractility of rat ventricular myocytes by 54.0 and 64.4%, respectively, compared with control, whereas R‐(+)‐MN9202 enhanced cell shortening by 10.1%. At 1 μmol/L, racemic MN9202 markedly reduced calcium transient (CaT) and L‐type Ca²⁺ channel current (I_Ca,L) by 60.0 and 50.7%, respectively, whereas the reductions in CaT and I_Ca,L produced by 1 μmol/L S‐(?)‐MN9202 were greater still (62.2 and 65.7%, respectively). In contrast, 1 μmol/L R‐(+)‐MN9202 increased CaT and I_Ca,L by 11.4 and 10.6%, respectively. Furthermore, findings from kinetics studies of I_Ca,L revealed that the steady state inactivation curve of I_Ca,L was shifted towards a hyperpolarizing potential by S‐(?)‐MN9202, but towards a depolarizing potential by R‐(+)‐MN9202. These results demonstrate different effects of R‐(+)‐MN9202 and S‐(?)‐MN9202. 3. In conclusion, the findings of the present study suggest that the chirality of MN9202 results in opposing pharmacological properties of its two enantiomers: S‐(?)‐MN9202 may be responsible for the therapeutic effects of racemic MN9202, whereas R‐(+)‐MN9202 contributes to it unwanted effects. The findings of the present study also indicate that MN9202 may be used as a new probe with which to investigate the structure–function relationships of Ca²⁺ channels.