Mechanism of NO Release

The mechanism of NO release from N-diazeniumdiolates is depicted in Fig. 3.7. If R , of the generic structure shown at the top is a cation, NO is generated spontaneously on protonation of the anionic portion along with the formation of dialkylamine. If R3 is covalently bound, it must be removed first to free the anion before spontaneous 

NO generation can begin. Some examples of masking the diazeniumdiolate ion in this way for pharmacological advantage are listed in Fig. 3.9 below [208]. 

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Fig. 12 Top Bfx with NO-releasing capability and stimulation of SGC. Middle Mechanism of NO release from Fx derivatives. Bottom Preparation of 3-furoxancarboxamide with good haemodynamic profile in vivo...

Fig. 13 Top Mechanism of NO release proposed for 3-furoxancarbonitrile derivatives. Middle Thiol induction of NO release from Fx 40. Bottom NO-releasing carbonitrile-Fxs and water-soluble-Fxs...

Amenates acylated at the exocydic nitrogen are stable as solid compounds but decompose in aqueous solutions releasing NO. This decomposition depends on the pH and most importantly on their chemical structure [147, 152]. The proposed mechanism of NO-release is shown in Scheme 6.24. It is related to that postulated for sydnonimines. The main difference is that here 5-substituted amenates 128 are able to react with water to form acyclic nitroso semicarbazides 129 directly without needing enzymatic cleavage, and these intermediates release NO by an oxidative or thiol mediated mechanism that is not fully understood [153]. 

Scheme 6.24 Proposed mechanism of NO release from mesoionic 1,2,3,4-oxatriazolium-5-amenates.

With the discovery that N O plays a role in vasodilation it has become important that nitrovasodilators (i.e. substances that act as vasodilators by the release of NO) are well-characterised. This includes a clear understanding of the mechanism of NO release. The use of an inappropriate agent may give non-reproducible or false data. At least three crucial factors must be considered when an NO-donor drug is selected ... 

Despite intense study of the chemical reactivity of the inorganic NO donor SNP with a number of electrophiles and nucleophiles (in particular thiols), the mechanism of NO release from this drug also remains incompletely understood. In biological systems, both enzymatic and non-enzymatic pathways appear to be involved [28]. Nitric oxide release is thought to be preceded by a one-electron reduction step followed by release of cyanide, and an inner-sphere charge transfer reaction between the ni-trosonium ion (NO+) and the ferrous iron (Fe2+). Upon addition of SNP to tissues, formation of iron nitrosyl complexes, which are in equilibrium with S-nitrosothiols, has been observed. A membrane-bound enzyme may be involved in the generation of NO from SNP in vascular tissue [35], but the exact nature of this reducing activity is unknown. 

Sodium nitroprusside was first prepared and investigated in the middle of the nineteenth century, and a comprehensive summary of the earlier chemical investigations has been published (17). Up to 1910-1930, the addition reactions of bases to NP were explored, involving the characterization of colored intermediates (e.g., with SH-, SR-, and SO3 ), useful for analytical purposes. The hypotensive action of NP was first demonstrated in 1929, and a considerable research effort has attempted to establish the mode of action of NP and its metabolic fate. Questions still arise on the mechanism of NO release from NP in the biological fluids, and we refer to them below. New accounts dealing with modern structural and reactivity issues associated with the coordination of nitrosyl in NP and other complexes have appeared (18-20). From the bioinorganic and environmental viewpoint, nitrosyl iron complexes have been studied with... 

The mechanisms of NO release from organic nitrates are complex, and still not fully explored. Figure 10.6, based on the scheme of Van de Voorde [7], dates back to the early 1990s but can be considered still valid after slight modification based on additional data [42]. It summarizes the proposed mechanisms by which NO-... 

Molsidomine itself is inactive. After oral intake, it is slowly converted into an active metabolite, linsidomine. The differential effectiveness in arterial vs. venous beds is less evident compared to the drugs mentioned above. Moreover, development of nitrate tolerance is of less concern. These differences i n activi ty profi le appear to reflect a different mechanism of NO release. The same applies to the following sodium nitroprusside. 

The proposed mechanism of NO release is shown in Scheme 1. Molsidomine (31) is converted to SIN-1 (32) by the action of liver esterases. SIN-1 (32) undergoes oxidation in the presence of oxygen or, in vivo, possibly by redox enzyme such as cytochrome c or by ferric myoglobin to release NO through a radical cation. 

In view of the fact that pharmacological effects of nitroprusside, [Fe(CN)5NO], a widely recognized hypotensive agent (61—65), have been attributed to the release of nitric oxide from its reduced form, i.e., [Fe(CN)5NO], the kinetic and thermodynamic properties of both nitrosyl complexes of pentacyanoferrate-(II) and -(III) have attracted considerable attention in the past two decades (66,67). In this context, the formation of [Fe(CN)5NO] and [Fe(CN)5NO] in the direct reactions of [Fe(CN)5(H20)] and [Fe(CN)5(Fl20)] with nitric oxide, respectively, was subjected to detailed kinetic and mechanistic investigations (68-70). As presented below, the results of these studies allowed to draw valuable conclusions concerning the validity of the mechanism of NO release from nitroprusside postulated in the Hterature. 

Figure 14 A Mechanism of NO release from diazeniumdiolated dibutylhexanediamine (DBHD/N2O2).

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