Syntheses, calcium channel agonist-antagonist modulation activities, and voltage-clamp studies of isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4- pyridinylpyridine-5-carboxylate racemates and enantiomers

Article abstract of DOI:10.1021/jm00015a007

A novel group of racemic isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4- pyridinylpyridine-5-carboxylate isomers [(±)-12-14] were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with isopropyl 3-aminocrotonate and 2-, 3-, or 4-pyridinecarboxaldehyde. Determination of their in vitro calcium channel-modulating activities using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays showed that the 2-pyridinyl isomer (±)-12 acted as a dual cardioselective calcium channel agonist (GPLA)/smooth muscle selective calcium channel antagonist (GPILSM). In contrast, the 3-pyridinyl [(±)-13] and 4-pyridinyl [(±)-14] isomers acted as calcium channel agonists on both GPLA and GPILSM. The agonist effect exhibited by (±)-12 on GPLA was inhibited by nifedipine and partially reversed by addition of extracellular Ca²⁺. In anesthetized rabbits, the 4-pyridinyl isomer (±)-14 exhibited a hypertensive effect that was qualitatively similar to that exhibited by the nonselective agonist Bay K 8644 and the 3-pyridinyl isomer (±)-13, whereas the 2-pyridinyl isomer (±)-12 induced a hypotensive effect similar to that of the calcium channel antagonist nifedipine. Similar results were obtained in a spontaneously hypertensive rat model. In vitro studies showed that the (+)-2-pyridinyl enantiomer (+)-12A exhibited agonist activity on both GPILSM and GPLA, but that the (-)-2-pyridinyl enantiomer (-)-12B exhibited agonist activity on GPLA and antagonist activity on GPILSM. Whole-cell voltage-clamp studies using isolated guinea pig ventricular myocytes indicated that (-)- 12B inhibited the calcium current (I(Ca)), that (+)-12A increased slightly I(Ca), and that (±)-12 inhibited I(Ca) but the latter inhibition was less than that for (-)-12B. (-)-12B effectively inhibited I(Ca) at all membrane potentials examined (-40-50 mV), whereas (+)-12A exhibited a weak agonist effect near the peak of the I-V curve. The 2-pyridinyl isomers (enantiomers) 12 represent a novel type of 1,4-dihydropyridine calcium channel modulator that could provide a potentially new approach to drug discovery targeted toward the treatment of congestive heart failure and probes to study the structure-function relationships of calcium channels.