Nitric Oxide Synthase Inhibitors

Abstract

Nitric oxide (NO) is an endogenic product from plants, bacteria, and animal cells that has many important effects in those organisms. It is produced by nitric oxide synthase (NOS), which is found in main three isoforms, namely endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS). It has an important role in homeostasis in different physiological systems, such as micro-and macro-vascularization, inhibition of platelet aggregation, and neurotransmission regulation in the central nervous, gastrointestinal, respiratory, and genitourinary systems. However, its overproduction has been associated with diseases such as arthritis, asthma, cerebral ischemia, Parkinson's disease, neurodegeneration, and seizures. For this reason, and due to better understanding of the molecular mechanisms by which NO provokes those diseases, the interest on the design of NOS inhibitors with therapeutic purposes has highly increased. Based on the foregoing considerations, the proposal of this chapter is to show an overview about the design strategies, mechanism of action at the molecular level, and the main advances toward the search for selective NOS inhibitors available in the literature.

Small-Molecule Inhibitors of Reactive Oxygen Species Production

“…We have chosen to focus on molecules that in our opinion constitute the most promising tools for studying NOS activity and function and that also show therapeutic potential. The reader is referred to refs and for a more comprehensive coverage of NOS inhibitors.…”

“…However, NOS isoform selectivity is a highly desirable characteristic of iNOS-targeting to avoid side-effects from nNOS or eNOS activity, such as hypertension. , 1400W ( 47 in Figure and Table ) is a selective human iNOS inhibitor that shows approximately 500 times lower activity in eNOS and more than 200 times selectivity over nNOS . 1400W has been found to penetrate tissues but unfortunately displays toxic effects in rats at high concentrations …”

“…19 A source of reactive nitrogen species is nitric oxide synthase (NOS), the enzyme responsible for the biosynthesis of nitric oxide and RNS derivatives. 20 NOS exists in three isoforms, two constitutively expressed and regulated by Ca 2+ and calmodulin (nNOS, neuronal nitric oxide synthase, and eNOS, endothelial nitric oxide synthase), and an inducible form, iNOS (inducible nitric oxide synthase). The isoforms have different cellular functions correlated to their different tissue localization.…”

Impact of Nitric Oxide Synthesis Modulators on the Cytokines Profile in Experimental Antiphospholipid Syndrome

“…At the same time, in the case of aminoguanidine administration a significant decrease in TNFα concentration was proved compare to the intact animals. According to EI Ferreira et al [23] aminoguanidine decreases TNFα levels, oxidative stress indicators, and NO metabolites.…”

The aminoguanidine effect on the content of cerebellar glial fibrillary acidic protein in experimental antiphospholipid syndrome with pregnancy

“…Однією із ланок, що відіграють роль у механізмах розвитку АФС, є система оксиду азоту (NO) [4]. NO синтезується з L-аргініну під впливом ферменту NO-синтази (NOS, КФ 1.14.13.39), яка існує в трьох ізоформахендотеліальна (eNOS), нейрональна (nNOS) та індуцибельна (iNOS) [5]. Роль NO в патогенезі АФС зумовлена як прямою, так і опосередкованою дією.…”