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

• Published in: Clinical and experimental pharmacology & physiology 2010-08, Vol.37 (8), p.817-825
• Main Authors: Li, Xiao-Qiang, Cao, Wei, Zeng, Ai-Guo, Yang, Zhi-Fu, Xing, Bin, Dong, Ling, Zhang, Hai-Feng, Mei, Qi-Bing
• Format: Article
• Language: English
• Subjects: Algorithms; Animals; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - pharmacology; Calcium Channels, L-Type - drug effects; Chromatography, High Pressure Liquid; Dihydropyridines - chemistry; Dihydropyridines - pharmacology; Electrophysiology; In Vitro Techniques; Kinetics; Male; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Nitrobenzenes - chemistry; Nitrobenzenes - pharmacology; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship
• ISSN: 1440-1681
• DOI: 10.1111/j.1440-1681.2010.05381.x

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 Ca(2+) 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 micromol/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 micromol/L, racemic MN9202 markedly reduced calcium transient (CaT) and L-type Ca(2+) channel current (I(Ca,L)) by 60.0 and 50.7%, respectively, whereas the reductions in CaT and I(Ca,L) produced by 1 micromol/L S-(-)-MN9202 were greater still (62.2 and 65.7%, respectively). In contrast, 1 micromol/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 Ca(2+) channels.