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| - Syntheses, Calcium Channel Agonist−Antagonist Modulation Activities, NitricOxide Release, and Voltage-Clamp Studies of 2-Nitrooxyethyl 1,4-Dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylateEnantiomers
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| - The novel (−)-(S)-2 and (+)-(R)-3 enantiomers of 2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate were synthesized for evaluation ascalcium channel modulators. Determination of their in vitro calcium-channel-modulatingactivities using guinea pig left atria (GPLA) and ileum longitudinal smooth muscle (GPILSM)showed that the (−)-(S)-2 enantiomer acted as a dual cardioselective calcium channel agonist(GPLA)/smooth muscle selective calcium channel antagonist (GPILSM). In contrast, the (+)-(R)-3 enantiomer exhibited calcium channel antagonist activity on both GPLA and GPILSM.The 2-nitrooxyethyl racemate is a nitric oxide (•NO) donor that released 2.7% •NO, relative tothe reference drug glyceryl trinitrate (5.3% •NO release/ONO2 moiety), in the presence ofN-acetylcysteamine. Whole-cell voltage-clamp studies using isolated guinea pig ventricularmyocytes indicated that both enantiomers inhibit calcium current but that the (−)-(S)-2enantiomer is a weaker antagonist than the (+)-(R)-3 enantiomer. These results indicate thatreplacement of the methyl ester substituent of (−)-(S)-methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate [(−)-(S)-1] by the 2-nitrooxyethyl ester •NOdonor substituent present in (−)-(S)-2 provides a useful drug design concept to abolish thecontraindicated calcium channel agonist effect of (−)-(S)-1 on vascular smooth muscle. Thenovel (−)-(S)-2 enantiomer is a useful lead compound for drug discovery targeted toward thetreatment of congestive heart failure, and it provides a useful probe to study the structure−function relationships of calcium channels.
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