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 (ICa), that (+)-12A increased slightly ICa, and that (+/-)-12 inhibited ICa but the latter inhibition was less than that for (-)-12B. (-)-12B effectively inhibited ICa 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.

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technique may make it possible to measure such temperatures directly and thereby to test the consistency of both theories.Finally, the extreme importance of nucleation, itself, in a wide range of scientific and technological disciplines, makes it of special interest to develop and apply the new technique. It is now possible to investigate nucleation in systems particularly free from contaminants and systems (especially in the case of solid-state transitions) that are virtually impossible to probe on such a time scale by other methods.

New biodegradable polyurethanes containing azo-linked polymeric prodrugs of 5-aminosalicylic acid (5-ASA) in the main chain were prepared by reacting 1,6-Hexamethylenediisocyanate (HDI) with 3,30-azobis(6-hydroxy benzoic acid) (ABHB) and 5-[4-(hydroxyl phenyl) azo] salicylic acid (HPAS) as azo derivatives of 5-ASA. The polymers were characterized by FTIR and 1H-NMR spectroscopy. The hydrolysis of polyurethane containing azoderivatives of 5-ASA was carried out in cellophane membrane dialysis bags containing aqueous buffer solution (pH 1/4 8.5 and pH 1/4 1) at 37 C. Detection of the hydrolysis product by UV spectroscopy showed that ABHB and HPAS were released by the hydrolysis of the urethane bond in the polymer chain.