Abstract:A recent uroselective R 1 -adrenoceptor antagonist, REC15/2739, has been joined with nitrooxy and furoxan NO-donor moieties to give new NO-donor R 1 -antagonists. All the compounds studied proved to be potent and selective ligands of human cloned R 1a -receptor subtype. Derivatives 6 and 7 were able to relax the prostatic portion of rat vas deferens contracted by (-)-noradrenaline because of both their R 1A -antagonist and their NO-donor properties.
“…All these NO donor hybrids were reviewed [2,17]. More recently, NO donor furoxans were also joined to 1,4-dihydropyridine Ca 2+ -channel activators [18], as well as to the REC15/2739, a uroselective α 1 -antagonist [19], and to the rabeprazole, a potent inhibitor of H + /K + -ATPase enzyme [20]. One of the problems that must be addressed when working with hybrid drugs is their balance.…”
Abstract:The article focuses attention on furoxan derivatives (1,2,5-oxadiazole 2-oxides) as NO donors. Possible mechanisms for NO release from these products in physiological solution and in segments of rabbit femoral artery are briefly considered. The in vitro antiaggregatory activities and the in vitro and in vivo vasodilating properties of a number of furoxans are examined with particular reference to involvement of NO in these actions. The use of the furoxan system to design new NO donor/drug hybrids is discussed in connection with the problem of the balance between NO-and drug-dependent activities of the resulting structures. Whether other biological activities (as yet, little studied) of furoxans, such as their antiparasite, antimicrobial, and antitumoral effects, are NO-dependent, is a matter still to be explored.
“…All these NO donor hybrids were reviewed [2,17]. More recently, NO donor furoxans were also joined to 1,4-dihydropyridine Ca 2+ -channel activators [18], as well as to the REC15/2739, a uroselective α 1 -antagonist [19], and to the rabeprazole, a potent inhibitor of H + /K + -ATPase enzyme [20]. One of the problems that must be addressed when working with hybrid drugs is their balance.…”
Abstract:The article focuses attention on furoxan derivatives (1,2,5-oxadiazole 2-oxides) as NO donors. Possible mechanisms for NO release from these products in physiological solution and in segments of rabbit femoral artery are briefly considered. The in vitro antiaggregatory activities and the in vitro and in vivo vasodilating properties of a number of furoxans are examined with particular reference to involvement of NO in these actions. The use of the furoxan system to design new NO donor/drug hybrids is discussed in connection with the problem of the balance between NO-and drug-dependent activities of the resulting structures. Whether other biological activities (as yet, little studied) of furoxans, such as their antiparasite, antimicrobial, and antitumoral effects, are NO-dependent, is a matter still to be explored.
“…For example, in the blood, S -nitrosoalbumin (SNO-albumin) and S -nitrosohemoglobin (SNO-Hb) have been reported to constitute the major conduits for circulating NO bioactivity, and the low-molecular-weight RSNOs, such as S -nitrosoglutathione (GSNO) (Figure ) and S -nitrosocysteine (CysNO), have been proposed as mediators of paracrine protein S-nitrosylation . Furthermore, S-nitrosylation can regulate protein function, as has been described for numerous proteins. − Therefore, the creation of synthetic donors, mimicking the endogenous low-molecular-weight RSNOs for research and therapeutic applications, has become extremely enticing. − 1 Structures of S -nitrosoglutathione (GSNO), S -nitroso- N -acetylpenicillamine (SNAP), and aryloxathiazolyliumolates.…”
S-Nitrosothiols (RSNOs) are important exogenous and endogenous sources of nitric oxide (NO) in biological systems. A series of 4-aryl-1,3,2-oxathiazolylium-5-olates derivatives with varying aryl para-substituents (-CF3, -H, -Cl, and -OCH3) were synthesized. These compounds were found to release NO under acidic condition (pH = 5). The decomposition pathway of the aryloxathiazolyliumolates proceeded via an acid-catalyzed ring-opening mechanism after which NO was released and an S-centered radical was generated. Electron paramagnetic resonance (EPR) spin trapping studies were performed to detect NO and the S-centered radical using the spin traps of iron(II) N-methyl-D-glucamine dithiocarbamate [(MGD)2-FeII] and 5,5-dimethyl-1-pyrroline N-oxide (DMPO). Also, EPR spin trapping and UV-vis spectrophotometry were used to analyze the effect of aryl para substitution on the NO-releasing property of aryloxathiazolyliumolates. The results showed that the presence of an electron-withdrawing substituent such as -CF3 enhanced the NO-releasing capability of the aryloxathiazolyliumolates, whereas an electron-donating substituent like methoxy (-OCH3) diminished it. Computational studies using density functional theory (DFT) at the PCM/B3LYP/6-31+G**//B3LYP/6-31G* level were used to rationalize the experimental observations. The aryloxathiazolyliumolates diminished susceptibility to reduction by ascorbate or gluthathione, and their capacity to cause vasodilation as compared to other S-nitrosothiols suggests potential application in biological systems.
“…Hybrid compounds 95 and 96, in which the structural features of the lead were joined with furoxan NO-donor moieties, were able to relax the prostatic portion of the rat vas deferens contracted by (-)-noradrenaline because of their α 1A -AR antagonist and NO-donor properties (Fig. 10) [77].…”
Native alpha(1)-adrenoreceptors (ARs) appear to exist as three different subtypes encoded by three genes, alpha(1A/1a), alpha(1B/1b), and alpha(1D/1d). Historically, the discovery of agents selective for each of the three alpha(1)-AR subtypes has been an active area of medicinal chemistry research because of the wide number of possible therapeutic applications. Initially introduced for the management of hypertension, alpha(1)-AR antagonists have, in fact, become increasingly common in the treatment of benign prostatic hyperplasia (BPH), and are effective therapeutic tools, when characterized by an appropriate uroselective profile. The majority of these derivatives display a competitive mechanism of action and belong to a variety of structural classes, but this review is focused on compounds belonging to the quinazoline, benzodioxane, arylpiperazine, and 1,4-dihydropyridine classes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
