SYNTHESIS, ROTAMER ORIENTATION, AND CALCIUM-CHANNEL MODULATION ACTIVITIES OF ALKYL AND 2-PHENETHYL 1,4-DIHYDRO-2,6-DIMETHYL-3-NITRO-4-(3- OR 6-SUBSTITUTED-2-PYRIDYL)-5-PYRIDINECARBOXYLATES

A group of racemic alkyl and a-phenethyl 1,4-dihydro-2,6-dimethyl-3-ni tro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates (13a-q) w as prepared using a modified Hantzsch reaction that involved the conde nsation of a 3- or 6-substituted-2-pyridinecarboxaldehyde (7a-j) with an alkyl or 2-phenethyl 3-aminocrotonate (11a-d) and nitroacetone (12) . Nuclear Overhauser (NOE) studies indicated there is a significant ro tamer fraction in solution where the pyridyl nitrogen is oriented abov e the 1,4-dihydropyridine ring, irrespective of whether a substituent is located at the 3- or 6-position. A potential Ii-bonding interaction between the pyridyl nitrogen free electron pair and the suitably posi tioned 1,4-dihydropyridine NH moiety may stabilize this rotamer orient ation. In vitro calcium channel antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. Compounds hav ing an i-Pr ester substituent acted as dual cardioselective calcium ch annel agonists (GPLA)/smooth muscle-selective calcium channel antagoni sts (GPILSM), except for the C-4 3-nitro-2-pyridyl compound which exhi bited an antagonist effect on both GPLA and GPILSM. In contrast, the c ompounds with a phenethyl ester group, which exhibited antagonist acti vity (IC50 = 10(-5)-10(-7) M range) on GPILSM, were devoid of cardiac agonist activity on GPLA. Structure-activity relationships showing the effect of a substituent (Me, CF3, Cl, NO2, Ph) at the 3- or 6-positio n of a C-4 2-pyridyl moiety and a variety of eater substituents (Me, E t, i-Pr, PhCH2CH2-) upon calcium channel modulation are described. Com pounds possessing a 3- or 6-substituted-2-pyridyl moiety, in conjuncti on with an i-Pr ester substituent, are novel 1,4-dihydropyridine calci um channel modulators that offer a new drug design approach directed t o the treatment of congestive heart failure and may also be useful as probes to study the structure-function relationships of calcium channe ls.