Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain

Mukherjee, Paramita; Cinelli, Maris A.; Kang, Soosung; Silverman, Richard B.

doi:10.1039/c3cs60467e

Cited by 136 publications

(122 citation statements)

References 251 publications

(403 reference statements)

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“…Its mechanism of action involves competitive inhibition of H 4 B cofactor, and series of related structures have been designed [11]. This compound has suppressed open-field behavior expressed as distance moved, exploratory rearing and grooming, suggesting that this compound can increase cortical excitability and interfere with some physiological and behavioral parameters [43].…”

Section: Neuronal Nitric Oxide Synthase (Nnos) Inhibitorsmentioning

confidence: 99%

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Nitric Oxide Synthase Inhibitors

Ferreira¹,

Serafim²

2017

Nitric Oxide Synthase - Simple Enzyme-Complex Roles

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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.

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Section: Neuronal Nitric Oxide Synthase (Nnos) Inhibitorsmentioning

confidence: 99%

“…Moreover, α-amino group of l-arginine interacts through H-bond with the heme propionate side chain, and the guanidine N-terminal nitrogen of this amino acid coordinates with Fe II (Figure 2). This ligand-receptor interaction profile is similar to all isoforms, which generates a challenge to selectivity [11]. [10].…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide Synthase Inhibitors

Ferreira¹,

Serafim²

2017

Nitric Oxide Synthase - Simple Enzyme-Complex Roles

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“…Some nNOS inhibitors which have shown promising efficacy and selectivity have undergone structural modifications in order to improve their PK properties and make them more attractive for clinical use. Previous reviews in this area have focused on the medicinal chemistry and SAR development of inhibitors for the three NOS isoforms [32,33]. This review will discuss the classes of inhibitors developed for each of the four nNOS therapeutic target sites, their potential interactions with the target site and the role computer aided drug design has played in the process of selective nNOS inhibition.…”

Section: Nos Binding Pockets and Ligand Designmentioning

confidence: 99%

Computational Development of Selective nNOS Inhibitors: Binding Modes and Pharmacokinetic Considerations

Curtin¹,

Kinsella²,

Stephens

2015

CMC

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Neuronal nitric oxide synthase (nNOS) produces the key signalling mediator nitric oxide, (NO). This gaseous, free radical molecule modulates a vast array of biological processes, from vascular pressure to immune responses and neurological signalling cascades. Overproduction of NO has been implicated in conditions including Alzheimer's disease, Parkinson's disease and schizophrenia. Inhibition of nNOS therefore offers a potential therapeutic approach for treatment of these conditions. This endeavour is made more complex by the fact that there are two other isoforms of nitric oxide synthase (NOS), endothelial NOS (eNOS) and inducible NOS (iNOS). The selectivity of nNOS inhibitors is therefore a key concern for therapeutic development. This review explores recent advances in the field of selective nNOS inhibition. A particular focus is placed on computational approaches towards the rational design of selective nNOS ligands with improved pharmacokinetic properties. These ligands have been targeted at four key binding sites of the nNOS enzyme -the tetrahydrobiopterin, calmodulin, nicotinamide adenine dinucleotide phosphate (NADPH) and arginine binding sites. The binding sites, and the compounds used to inhibit them, will be discussed in turn, along with the computational methods which have been employed in the field of nNOS inhibition.

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“…L-NAME would be expected to inhibit nNOS, eNOS and, to a lesser extent, iNOS activity. By contrast, ADMA (10 µM) would be expected to inhibit eNOS activity, and not iNOS activity (66).…”

Section: C B Amentioning

confidence: 99%

Effects of nitric oxide synthase deficiency on a disintegrin and metalloproteinase domain-containing protein 12 expression in mouse brain samples

Lendeckel¹,

Wolke²,

Bernstein

et al. 2015

Molecular Medicine Reports

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Abstract.A d isi nt eg r i n a nd met a l loprot ei nase domain-containing protein 12 (ADAM12) belongs to the ADAM family of transmembrane proteins. Via proteolysis, cell adhesion, cell-cell fusion, cell-matrix interaction and membrane protein shedding, ADAM proteins are involved in normal brain development, and also in cancer genesis and progression, and in inflammation. Therefore, neurobiological research focusing on this protein is increasing. Nitric oxide (NO), which is endogenously produced by NO synthases (NOS), is associated with glial tumors. However, knock-out of NOS produces only limited antitumor effects. The present study analyzed the expression of ADAM12 in the cortex and hippocampus of C57/BL6 wild-type mice, and endothelial NOS-, neuronal NOS-(nNOS) or inducible NOS (iNOS)-deficient ( -/-) mice, at different stages of development. Expression of ADAM12 was quantified using immunoblot analysis of cortical and hippocampal tissue samples from fetal, neonatal (5 days postnatal), adult (12 weeks old) or >1 year old mice. Using reverse transcription-quantitative polymerase chain reaction, ADAM12 expression was analyzed in cultured N9, OLN93, C6 and PC12 cells, representing the four main cell types in the brain, following NOS inhibition. ADAM12 expression was low in all mouse genotypes and regions of the brain, and in fetal and neonatal mice, an increase in expression was observed with increasing age. The highest levels of expression were observed in the cortex of adult mice, iNOS -/-mice of >1 year and wild-type mice, and in the hippocampus of adult and iNOS -/-mice of >1 year. By contrast, ADAM12 expression was lowest in adult nNOS -/-mice. Inhibition of NOS using N ω -Nitro-L-arginine methyl ester hydrochloride, induced ADAM12 mRNA expression in N9 and PC12 cell lines. Inhibition of NOS using L-N 6 -(1-Iminoethyl)lysine dihydrochloride, induced ADAM12 mRNA expression in N9 and C6 cell lines. No change in ADAM12 expression was observed in OLN93 cells following NOS inhibition. ADAM12 expression in mouse hippocampus and cortex samples demonstrated considerable variation during development, with a marked increase observed in adult and >1 year old mice, compared with that in fetal and neonatal mice. IntroductionNitric oxide (NO) is an important signaling molecule found in animals, including humans. Reduced NO production is associated with important cardiovascular risk factors, such as hyperlipidemia (1,2), diabetes, hypertension, smoking, atherosclerosis and aging (3). The bioavailability of NO in cells and tissues decreases with age. This may be a result of a decrease in the expression of the constitutive isoforms [endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS)], with age (4). Inducible NOS (iNOS)-mediated NO formation has been shown to affect longevity. In mice, iNOS overexpression may lead to increased mortality, which is associated with cardiac hypertrophy and sudden cardiac death as a result of bradyarrhythmias (5). iNOS expression is typically not observed in the brains of young (1-3...

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Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain

Cited by 136 publications

References 251 publications

Nitric Oxide Synthase Inhibitors

Nitric Oxide Synthase Inhibitors

Computational Development of Selective nNOS Inhibitors: Binding Modes and Pharmacokinetic Considerations

Effects of nitric oxide synthase deficiency on a disintegrin and metalloproteinase domain-containing protein 12 expression in mouse brain samples

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