Complexes of .NO with nucleophiles as agents for the controlled biological release of nitric oxide. Vasorelaxant effects
Abstract
Selected nucleophile/nitric oxide adducts [compounds which contain the anionic moiety, XN(O-)N = O] were studied for their ability to release nitric oxide spontaneously in aqueous solution and for possible vasoactivity. The diversity of structures chosen included those in which the nucleophile residue, X, was that of a secondary amine [Et2N, as in [Et2NN(N = O)O]Na, 1], a primary amine [iPrHN, as in [iPrHNN(N = O)O]Na, 2], a polyamine, spermine [as in the zwitterion H2N(CH2)3NH2+(CH2)4N[N(N = O)O-](CH2)3NH2, 3], oxide [as in Na[ON(N = O)O]Na, 4], and sulfite [as in NH4[O3SN(N = O)O]NH4, 5]. The rate constants (k) for decomposition in pH 7.4 phosphate buffer at 37 degrees C, as measured by following loss of chromophore at 230-260 nm, were as follows: 1, 5.4 x 10(-3) s-1; 2, 5.1 x 10(-3) s-1; 3, 0.30 x 10(-3) s-1; 4, 5.0 x 10(-3) s-1; and 5, 1.7 x 10(-3) s-1. The corresponding extents of nitric oxide release (ENO) were 1.5, 0.73, 1.9, 0.54, and 0.001 mol/mol of starting material consumed, respectively, as determined from the integrated chemiluminescence response. Vasodilatory activities expressed as the concentrations required to induce 50% relaxation in norepinephrine-constricted aortic rings bathed in pH 7.4 buffer at 37 degrees C (EC50) were as follows: 1, 0.19 microM; 2, 0.45 microM; 3, 6.2 microM; 4, 0.59 microM; and 5, 62 microM. Vasorelaxant potency (expressed as 1/EC50) was strongly correlated with the quantity of .NO calculated from the physicochemical data to be released in the interval required to achieve maximum relaxation at the EC50 doses (r = 0.995). This suggests that such nucleophile/.NO adducts might generally be useful as vehicles for the nonenzymatic generation of nitric oxide, in predictable amounts and at predictable rates, for biological purposes. The particular significance for possible drug design is underscored in the very favorable potency comparison between several of these agents and the established nitrovasodilators sodium nitroprusside and glyceryl trinitrate (EC50 values of 2.0 and greater than 10 microM, respectively) in parallel aortic ring tests.
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Diazeniumdiolate compounds may form carcinogenic nitrosamines.
“One drawback of the diazeniumdiolate compounds is that they may potentially form carcinogenic nitrosamines.151,152”
From Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO) (2016) · cites this paper as [151]
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- Authors
- Maragos, C. M., Morley, D., Wink, D. A., Dunams, T. M., Saavedra, J. E., Hoffman, A., Bove, A. A., Isaac, L., Hrabie, J. A., & Keefer, L. K.
- Affiliations
- Frederick National Laboratory for Cancer Research (US)
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1991-11
- Volume
- 34
- Issue
- 11
- Pages
- 3242-3247
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W1998879311
- Cited by
- 722
- References
- 17
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 4 · 2023: 10 · 2022: 5 · 2021: 13 · 2020: 13 · 2019: 16 · 2018: 14 · 2017: 11 · 2016: 15 · 2015: 14 · 2014: 19 · 2013: 23 · 2012: 21
- FWCI
- 5.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01co074102-094)
- National Cancer Institute (N01CO-74102)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Physical Sciences › Chemistry › Organic Chemistry › Structural and Chemical Analysis of Organic and Inorganic Compounds
- Physical Sciences › Chemistry › Organic Chemistry › Free Radicals and Antioxidants
- Keywords
- nitric oxide donors, nitric oxide release, controlled release, vasorelaxation, vasodilation, aortic rings, norepinephrine-induced contraction, spermine, amine adducts, decomposition kinetics, chemiluminescence, zwitterion, polyamines
- MeSH terms
- Animals, Kinetics, Muscle, Smooth, Vascular, Nitric Oxide, Nitro Compounds, Rabbits, Vasodilator Agents
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