Nitric oxide (•NO), a highly reactive, diffusible, and unstable radical plays an important role in the regulation of a wide range of physiological processes, including cellular immunity, angiogenesis, neurotransmission, and platelet aggregation. •NO is synthesized from L-arginine by the action of nitric oxide synthases (NOS) in a two-step oxidation process. Free •NO is a transient species with a half-life of only about five seconds. Hence, most studies on •NO actions are based on the activity of NOS. Researchers have always sought relatively stable •NO donors with potential therapeutic value. In considering the biological or therapeutic value of any •NO donor, one must take several factors into consideration. One must be able to control the rate and the amount of •NO released; the by-products of the reaction should have minimal side effects; and the release of •NO should not be affected by common biochemical factors. Additionally, the quantities of •NO delivered must be large enough to achieve the desired physiological effects. It may be possible to accomplish this through local administration of •NO-releasing compounds, such as a carotid artery infusion to reverse cerebral vasospasm or transurethral administration to treat impotency. To effectively use •NO-based drugs, development of •NO-based prodrugs, with protective groups attached, may be necessary to obtain a targeted release of •NO.

Synthetic chemical reagents that release •NO, continuously over a period of time, under physiological conditions, have been in use for a long time in clinical management of cardiovascular diseases. Among the most widely used •NO donors are organic nitrates (for e.g., glycerin trinitrate) and nitrites, and furoxan derivatives. These donors require thiols as a cofactor for generating •NO and can use endogenous sources of thiols. Here •NO is first transferred to thiol and it is then released from the Snitrosothiol. Hence, the thiol derivative becomes a true •NO donor. Therefore, under conditions of thiol depletion (as in extreme oxidative stress) additional doses of organic nitrates do not provide any •NO activity.

A number of •NO donors have been developed to augment the action of intracellularly released •NO, which are also known to stimulate guanylate cyclase activity. Some of the known natural carriers of •NO are S-nitrosoglutathione and S-nitrosocysteine. Upon conversion of thiols to S-nitrosothiols, •NO is released by a homolytic break of the S-N bond (2 RS-NO → RS-SR + 2 •NO). The bioaction of S-nitrosothiols is reported to be similar to that of •NO in most cases. However, The use of S-nitrosothiols has a disadvantage in that they are too unstable to be used as long term •NO donors. S-Nitroso-N-penicillamine (SNAP) offers somewhat higher stability when compared to other nitroso compounds. Although the release of •NO is spontaneous, it is somewhat sustained. Glyco-SNAPs are more stable analogs of SNAP and the release of •NO can be monitored over a period of 24 to 30 hours. Maragos et al. developed a versatile group of stabilized •NO-amine complexes known as NOC compounds. These donors release •NO spontaneously without the influence of any cofactors. They act as intramolecular zwitterions, stabilized with an intramolecular hydrogen bond through dispersion of the negative charge, which prevents protonation. In these compounds the rate of •NO release is, therefore, dependent upon the weakness of the hydrogen bond. These compounds, when dissolved in aqueous medium, such as buffer, plasma, or cell culture medium, dissociate to form two •NO molecules and one molecule of the corresponding amine. The •NO release follows the first-order kinetics and the half-life of •NO release varies from a few minutes to several hours. Another important point to note here is that •NO is released from NOC compounds at much higher rate at lower pH values. Therefore, it is advantageous to prepare a slightly alkaline solution of NOC, which can be then added to the sample buffer or the culture medium. The alkaline stock solution is stable, at the most, for a day.

A new series of •NO donors known as the NOR compounds has been developed. These non-thiol-based compounds release •NO spontaneously, under physiological conditions, in a rate-controlling manner and their by-products do not exhibit any significant biological activity. The pattern of •NO release is very similar to that of NOC series of compounds and follows the first-order kinetics. The half-life of NOR compounds varies from a few minutes to a few hours. Therefore, one can select the appropriate NOR compound to control the release of •NO. NOR compounds are relatively stable in anhydrous organic solvents.