SYNTHESIS AND CALCIUM CHANNEL-MODULATING EFFECTS OF ALKYL (OR CYCLOALKYL) 6-DIMETHYL-3-NITRO-4-PYRIDYL-5-PYRIDINECARBOXYLATE RACEMATES AND ENANTIOMERS

A group of racemic alkyl (or cycloalkyl) 1,4-dihydro-2,6-dimethyl-3-ni tro-4-(2-, 3-, or 4-pyridyl)-5-pyridinecarboxylate isomers (6-14) were prepared using a modified Hantzsch reaction that involved the condens ation of nitroacetone with an alkyl (or cycloalkyl) 3-aminocrotonate a nd 2-, 3 -, or 4-pyridinecarboxaldehyde. Determination of their in vit ro calcium channel-modulating activities using guinea pig ileum longit udinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays showed that the 2-pyridyl isomers acted as dual cardioselective calci um channel agonists (GPLA)/smooth muscle selective calcium channel ant agonists (GPILSM). In contrast, the 3-pyridyl and 4-pyridyl isomers ac ted as calcium channel agonists on both GPLA and GPILSM. In the C-4 2- pyridyl group of compounds, the size of the C-5 alkyl (or cycloalkyl) ester substituent was a determinant of GPILSM antagonist activity wher e the relative activity profile was cyclopentyl and cyclohexyl > t-Bu, i-Bu, and Et 1 MeOCH2CH2 > Me. The point of attachment of the C-4 pyr idyl substituent was a determinant of GPLA agonist activity where the potency order was generally 4- and 3-pyridyl > 2-pyridyl. (+)-Cyclohex yl methyl-3-nitro-4-(2-pyridyl)-5-pyridinecarboxylate [(+)-14a] was a less potent calcium antagonist ((IC50 = 5.27 x 10(-6) M) than the (-)- enantiomer (IC50 = 7.48 x 10(-8) M) on GPILSM. In the GPLA assay, (+)- 14a exhibited a much more potent agonist effect (EC50 = 8.45 x 10(-6) M) relative to the marginal agonist effect produced by(-)-14a. The C-4 2-pyridyl compounds (enantiomers) constitute a novel type of 1,4-dihy dropyridine calcium channel modulator that could provide a new drug de sign concept directed toward the treatment of congestive heart failure , and for use as probes to study the structure-function relationships of calcium channels.