AbstractA group of racemic nitrooxyalkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐pyridinecarboxylates 8a–o were synthesized using modified Hantzsch reactions. In vitro calcium channel antagonist activities, determined using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay, showed that compounds 8a–o exhibited weaker calcium antagonist activity (10–5 to 10–7 M range) than the reference drug nifedipine (IC50 = 1.43 × 10–8 M). Compounds 8 possessing a C‐4 R1 = 2‐pyridyl substituent were always more potent than the approximately equiactive analogs having an R1 = 3‐pyridyl, 4‐pyridyl or 2‐CF3‐C6H4‐substituent, within each subgroup of nitrooxyalkyl compounds [R2 = – (CH2)nONO2 (n = 2, 3, 4) or –CH(CH2ONO2)2]. Although the length of the R2 = –(CH2)nONO2 substituent (n = 2–4) was not a determinant of smooth muscle calcium antagonist activity when the C‐4 R1‐substituent was 2‐pyridyl, when R1 was a 3‐pyridyl, 4‐pyridyl, or 2‐CF3‐C6H4‐substituent, the relative potency order with respect to the R2 = –(CH2)nONO2 substituent was n = 3 and 4 > n = 2. Replacement of the isopropyl substituent of the ester moiety of the calcium antagonist (±)‐2‐pyridyl 3a by a –(CH2)nONO2 (n = 2–4) moiety increased calcium antagonist activity on GPILSM by 8‐fold. In contrast, replacement of the isopropyl substituent of the ester moiety of the calcium agonists (±)‐3‐pyridyl 3b, (±)‐4‐pyridyl 3c or the methyl substituent of the ester moiety of Bay K8644 by a R2 nitrooxyalkyl substituent resulted in abolition of their calcium agonist effects on GPILSM that is replaced by a smooth muscle calcium antagonist effect. These calcium antagonist data support the concept that incorporation of a nitrooxyalkyl ester substituent constitutes a valuable drug design strategy to enhance Hantzsch 1,4‐dihydropyridine calcium antagonist and/or abolish calcium agonist effects on smooth muscle. Replacement of the isopropyl (8b–c), or the methyl (8d) group by a –CH2CH2ONO2 moiety resulted in retention of the cardiac positive inotropic effect where the relative potency order with respect to the C‐4 substituent was 2‐CF3‐C6H6‐ (8d) > 3‐pyridyl (8b) ≈ 4‐pyridyl (8c). Model hybrid (calcium channel modulation, ·NO release) compounds, that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4‐dihydropyridine CC modulator that offers a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure–function relationship of calcium channels. Drug Dev. Res. 51:225–232, 2000. © 2001 Wiley‐Liss, Inc.