Previously, it was shown that the D enantiomer of isoidide dinitrate was 10-fold more potent than the L enantiomer and 10-fold less potent than glyceryl trinitrate for stimulating cyclic GMP accumulation and relaxation of isolated rat aorta. In the present study, these organic nitrates were tested for their ability to induce tolerance to organic nitrate-induced relaxation, cyclic GMP accumulation, and guanylate cyclase activation in rat aorta in vitro. To compensate for the differences in vasodilator potency, tolerance was induced by incubating isolated rat aorta with concentrations of organic nitrates 1,000-fold greater than the EC50 for relaxation. Under these conditions, the EC50 for relaxation was increased significantly for each organic nitrate and to a similar degree on subsequent reexposure. These data suggest that the potential for inducing in vitro tolerance to relaxation was the same for the three organic nitrates tested. When activation of soluble guanylate cyclase by these compounds was assessed, the enantiomers of isoidide dinitrate were equipotent, but less potent than glyceryl trinitrate, suggesting that the site of enantioselectivity is not guanylate cyclase itself. In blood vessels made tolerant to organic nitrates by pretreatment with glyceryl trinitrate, vasodilator activity, cyclic GMP accumulation, and guanylate cyclase activation were attenuated on reexposure to each organic nitrate. In addition, differences in the potency of the three organic nitrates and the enantioselectivity of isoidide dinitrate for relaxation were abolished in tolerant tissue, whereas the potency difference between glyceryl trinitrate and isoidide dinitrate for activation of guanylate cyclase was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

In the presence of chiral environment compounds, C, optical rotation is induced in symmetric substrates, S, and may be detected as circular dichroism in the electronic spectra of the solutions. Thus the n-?I* transitions of symmetric and racemic carbonyl compounds, and of symmetric nitro and azo compounds, become optically active when these S are dissolved in chiral hydrocarbons, ketones, or carbinols, or in solutions of these C in achiral solvents. The rotational strengths of the induced circular dichroism bands of S are solvent, temperature, and concentration dependent. Only limited correlation of the sign and magnitude of the induced bands with the stereochemistry of C and S is evident on the data so far accumulated. Halogenated achiral solvents enhance the intensity, and, in some cases reverse the sign of the induced bands.A new mechanism of asymmetric induction is proposed in which specific bonding of C with S is not prerequisite.

In the infrared spectra of mono- and di-nitrate esters of the l,4;3,6-dianhydrides of d-mannitol, d-glucitol, and l-iditol in benzene solution (0.04 M in nitrato groups), the frequencies of the va(NO2) and v(ON) bands (singlets) were 1 645 ± 3 and 843 ± 3 cm−1, respectively, whereas the vs(NO2) band occurred at frequencies characteristic of either an endo (1 282 ± 1 cm−1) or an exo (1 274 ± 1 cm−1) configuration of the nitrato group; the ratios of the band areas were 1.5:1.0:1.0, respectively.The stereospecific frequency of the vs(NO2) band was attributed to non-bonded intramolecular interaction between the nitrato group and vicinal oxy groups on the basis of the spectra run in a series of solvents and the molecular conformations determined by X-ray crystallography. This new stereochemical probe permitted the assignment of the structure, configuration, and conformation in a series of nitrate esters.

No abstract

In contrast to the rapid and selective replacement of a secondary 0-nitro group by hydrogen in the hexitol hexanitrates a t 25-50' C, the dinitrate esters of the 1,4;3,6-dianhydrides of D-n~annitol, D-glLIcitoI, and L-iditol (cis-isohexides) reacted slowly in anhydrous pyridine a t 87-115" C. The chief products were a polymer, nitrogen oxides, and pyridinium nitrate; the yield of mononitrates did not exceed lOyo and none of the parent diols were formed.The relative rates of the first-order decon~position of the nitroxy groups in the isomeric dinitrates were in reverse order to that for S N~ reaction a t carbon in these compounds.Activation energies and frequency factors were determined and water was shown to have a retarding effect.Thermal decomposition of the dinitrates in solution in nitrobenzene, nl-xylene, or syintetrachloroethane was much slower than the pyridine reaction a t the same temperature and was independent of the polarity of the solvent and the conformation of the ester. INTRODUCTIONDulcitol and D-inannitol hexanitrates have been shown to react selectively with pyridine to yield the corresponding 1,2,4,5,6-pentanitrates (1, 2). The rate of reaction was different for the two hexitol derivatives and the resulting pentanitrates were essentially stable to pyridine under the same conditions. Sorbitol hexanitrate reacted similarly with pyridine but the pentanitrate was not fully characterized (3). The reaction was inconveniently fast for kinetic studies even a t 25" C and the n~ultiplicity of nitroxy groups and inolecular conformations further complicated the problem of sorting out the reaction mechanism.The three known isomeric 1,4;3,6-dianhydrohexitols (the cis-isohexides) and their derivatives have been shown to behave characteristically in certain types of reactions clue to differences in their restricted conformations (4, 5 ) . In an attempt to determine the mechanism of the pyridine -nitrate ester reaction the dinitrates of the isohexides (1-111, Fig. 1) were selected for study since observation of similar steric effects in their reactions with pyridine would aid in diagnosis of the type of mechanism involved. The presence of only two, non-vicinal, secondary, nitroxy groups in these isomers was also expected t o simplify analysis of the results. RESULTS A N D DISCUSSIONThe three isohexide dinitrates (Fig. 1) were prepared in crystalline form and characterized through their nitrogen contents, infrared spectra, and nearly quantitative conversion to the parent diols. The physical constants and nitrogen contents of the isomers are show11 in Table I. The dinitrates dissolved readily in pyridine and the colorless solutions were stable over several weeks a t roorn temperature. No vigorous reaction occurred on heating under reflux; however, slow decomposition, accoinpailied by a red coloration of the solution and evolution of oxides of nitrogen, began a t temperatures above 50" C.At 115" C 0.424 M solutions of the isohexide dinitrates in anhydrous pyridine decoinposed according to an apparent firs...