A new class of nitric oxide‐releasing derivatives of cetirizine; pharmacological profile in vascular and airway smooth muscle preparations

Abstract

Background and purpose: The pharmacological properties of compounds NCX 1512 and NCX 1514, synthesized by linking the histamine H1-receptor antagonist cetirizine to NO-releasing spacer groups, are reported. The aim was to establish if the compounds retained the antihistamine action of the parent compound, to assess their efficacy as NO donors and to test if they had broader antiallergic activity than cetirizine in the lung. Experimental approach: Antihistamine activity of NCX 1512 and NCX 1514 was investigated in vitro in the guinea pig ileum, in tracheal rings (GPTR) and lung parenchymal strips (GPLP) of the guinea-pig. The NO-releasing capacity was investigated in vascular preparations; the isolated rabbit and guinea-pig aorta and guinea-pig pulmonary artery. Kinetics of NO release were assessed in a rat whole blood assay. Key results: Both NCX 1512 and NCX 1514 retained activity as H1-receptor antagonists in the guinea pig ileum and airway preparations. The NO-releasing NCX compounds relaxed the rabbit aorta, an action prevented by the guanylyl cyclase inhibitor ODQ (10 mM). NCX 1512 and NCX 1514 did not relax the antigen (ovalbumin) pre-contracted GPTR, whereas the NO donors NCX 2057 and DEA-NONOate relaxed guinea-pig pre-contracted vascular and tracheal preparations. Cetirizine (1-100 mM) and NCX 1512 (1-100 mM) reduced the cumulative (0.01-100 mg ml À1 ) ovalbumin-induced constriction in GPTR, but had no significant effect in GPLP. Conclusions and implications: NCX 1512 and NCX 1514 act as antihistamines and NO donors. However, there was no improved effect compared to cetirizine on antigen-induced constriction of the central and peripheral lung. (2007) British Journal of Pharmacology

NO and HNO donors, nitrones, and nitroxides: Past, present, and future

“…Although several types of • NO donors have been reported over the years, sodium nitroprusside (SPN) and organic nitrates like glyceryl trinitrate (GTN), isosorbide mononitrate (ISMN), and pentaerythrityl tetranitrate (PETN) (Fig. ) remain the most relevant for the treatment of cardiovascular‐related events, namely as vasodilators …”

“…Nitric oxide ( • NO) is a signaling molecule that regulates a wide range of important cellular functions such as vascular tone, platelet aggregation, angiogenesis, cell differentiation and death, neurotransmission, and immune response …”

“…• NO, an innovative strategy based on the development of • NO donors has emerged in the 1990s. This strategy enables radical stabilization and controlled • NO release at the target sites 1,2,28. Only molecules with the general motif of X-N = O are direct…”

iNOS affects matrix production in distal lung fibroblasts from patients with mild asthma

“…It is therefore tempting to speculate that NO could have a modulatory role in distal airway remodelling. In support of a modulatory effect of NO in distal airways, iNOS inhibition was found to cause enhanced antigen-induced contractions and increased cysteinyl-leukotriene release in guinea pig lung parenchymal strips (54), whereas addition of exogenous NO showed modest dilatory effect in the distal lung compared to more proximal airways and pulmonary arteries (55,56). In a transgenic mice model overexpressing iNOS, NO was found to have beneficial effects on lung function and that endogenous NO per se did not cause airway inflammation (57).…”

Metabolism and Pathways for Denitration of Organic Nitrates in the Human Liver

“…Nitrooxybutyl-ester derivatives of anti-inflammatory and/or antioxidant agents, such as flurbiprofen and ferulic acid, is a novel class of organic nitrates with potential therapeutic implication in a variety of different conditions (Keeble and Moore, 2002;Scatena, 2004), such as neurodegenerative diseases (Wenk et al, 2002(Wenk et al, , 2004Prosperi et al, 2004;Gasparini et al, 2005), inflammation and nociception (Ronchetti et al, 2009), learning and memory (Boultadakis et al, 2010), airway inflammation and relaxation (Larsson et al, 2007(Larsson et al, , 2009, osteoporosis, and bone resorption (Idris et al, 2004). Despite extensive pharmacological characterization of these compounds, their metabolism and pathways of denitration remain unknown.…”