LF 16.0335, a novel potent and selective nonpeptide antagonist of the human bradykinin B<sub>2</sub> receptor

Pruneau, Didier; Luccarini, Jean‐Michel; Fouchet, Chantal; Defrêne, Evelyne; Franck, Rose‐Marie; Loillier, Bruno; Duclos, H; Robert, Claude; Cremers, Béatrice; Bélichard, Pierre; Paquet, Jean‐Luc

doi:10.1038/sj.bjp.0702083

Cited by 27 publications

(23 citation statements)

References 46 publications

(53 reference statements)

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“…Competitive binding assays were performed as described previously (Sheen et al, 1985;Pruneau et al, 1998). MCF-7 human breast cancer cells were used as the source of estrogen receptor, and Chinese hamster ovary cells were used as the source of bradykinin B 2 receptor.…”

Section: Methodsmentioning

confidence: 99%

Sesamin Metabolites Induce an Endothelial Nitric Oxide-Dependent Vasorelaxation through Their Antioxidative Property-Independent Mechanisms: Possible Involvement of the Metabolites in the Antihypertensive Effect of Sesamin

Nakano¹,

Kwak²,

Fujii³

et al. 2006

J Pharmacol Exp Ther

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Sesamin, a major lignan in sesame seeds and oil, has been known to lower blood pressure in several types of experimental hypertensive animals. A recent study demonstrated that sesamin metabolites had in vitro radical-scavenging activities. Thus, we determined whether the antioxidative effect of sesamin metabolites modulate the vascular tone and contribute to the in vivo antihypertensive effect of sesamin. We used four demethylated sesamin metabolites: SC-1m (piperitol), SC-1 (demethylpiperitol), SC-2m [(1R,2S,5R,6S)-6-(4-hydroxy-3-methoxyphenyl)-2-(3,4-dihydroxyphenyl)-3,7-dioxabicyclo [3,3,0]octane], and SC-2 [(1R,2S,5R, 6S)-2,6-bis (3,4-dihydroxyphenyl)-3,7-dioxabicyclo-[3,3,0]octane]. SC-1, SC-2m, and SC-2, but not SC-1m, exhibited potent radicalscavenging activities against the xanthine/xanthine oxidaseinduced superoxide production. On the other hand, SC-1m, SC-1, and SC-2m produced endothelium-dependent vasorelaxation in phenylephrine-precontracted rat aortic rings, whereas SC-2 had no effect. The SC-1m-and SC-1-induced vasorelaxations were markedly attenuated by pretreatment with a nitric oxide synthaseNeither SC-1m nor SC-1 changed the expression level of endothelial NOS protein in aortic tissues. The antihypertensive effects of sesamin feeding were not observed in chronically NO-ARG-treated rats or in deoxycorticosterone acetate-salt-treated endothelial NOS-deficient mice. These findings suggest that the enhancement of endothelium-dependent vasorelaxation induced by sesamin metabolites is one of the important mechanisms of the in vivo antihypertensive effect of sesamin.Endothelium-derived nitric oxide (NO) is a potent vasodilator. NO synthesized by endothelial NO synthase (eNOS) diffuses into the smooth muscle cells and stimulates the soluble guanylate cyclase (sGC), leading to increased cGMP production and smooth muscle relaxation (Moncada and Higgs, 1993). Several findings have suggested that excess superoxide (O 2 . ) produced in vascular cells interacts with NO, induces the abnormality of vascular tonus regulation, and results in the development of hypertension (Rajagopalan et al., 1996;Jung et al., 2004). In addition, Laursen et al. (1997) reported that both the development of hypertension and the altered endothelium-dependent vascular relaxation were improved by the treatment with membrane-targeted forms of superoxide dismutase in angiotensin II-induced hypertensive rats. Thus, it seems likely that the suppression of oxidative stress improves the NO bioavailability and prevents the development of hypertension and end-organ damage (Zhou et al., 2003;Schmieder, 2005). Sesamin ( Fig. 1) is one of the lignans found in high concentration in sesame seeds and oil. We have obtained evidence that dietary sesamin efficiently suppressed the development and maintenance of hypertension in deoxycorticoArticle, publication date, and citation information can be found at

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Section: Methodsmentioning

confidence: 99%

Sesamin Metabolites Induce an Endothelial Nitric Oxide-Dependent Vasorelaxation through Their Antioxidative Property-Independent Mechanisms: Possible Involvement of the Metabolites in the Antihypertensive Effect of Sesamin

Nakano¹,

Kwak²,

Fujii³

et al. 2006

J Pharmacol Exp Ther

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“…B2 antagonism assays were carried out following a protocol described elsewhere [34]. Specifically, compounds were tested on human recombinant bradykinin B2 receptors expressed in CHO cells.…”

Section: Binding Assaysmentioning

confidence: 99%

New insights into the stereochemical requirements of the bradykinin B1 receptor antagonists binding

Lupala

Gómez-Gutiérrez

Pérez

2016

Journal of Molecular Graphics and Modelling

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Abstract:Bradykinin (BK) is a member of the kinin family, released in response to inflammation, trauma, burns, shock, allergy and some cardiovascular diseases, provoking vasodilatation and increased vascular permeability among other effects. Their actions are mediated through at least two G-protein coupled receptors, B1 a receptor upregulated during inflammation episodes or tissue trauma and B2 that is constitutively expressed in a variety of cell types. The goal of the present work is to carry out a structure-activity study of BK B2 antagonism, taking into account the stereochemical features of diverse non-peptide antagonists and the way these features translate into ligand anchoring points to complementary regions of the receptor, through the analysis of the respective ligand-receptor complex. For this purpose an atomistic model of the BK B2 receptor was built by homology modeling and subsequently refined embedded in a lipid bilayer by means of a 600 ns molecular dynamics trajectory. The average structure from the last hundred nanoseconds of the molecular dynamics trajectory was energy minimized and used as model of the receptor for docking studies. For this purpose, a set of compounds with antagonistic profile, covering maximal diversity were selected from the literature. Specifically, the set of compounds include Fasitibant, FR173657, Anatibant, WIN64338, Bradyzide, CHEMBL442294, and JSM10292. Molecules were docked into the BK B2 receptor model and the corresponding complexes analyzed to understand ligand-receptor interactions. The outcome of this study is summarized in a 3D pharmacophore that explains the observed structureactivity results and provides insight into the design of novel molecules with antagonistic profile. To prove the validity of the pharmacophore hypothesized a virtual screening process was also carried out. The pharmacophore was used as query to identify new hits using diverse databases of molecules. The results of this study revealed a set of new hits with structures not connected to the molecules used for pharmacophore development. A few of these structures were purchased and tested. The results of the binding studies show about a 33% success rate with a correlation between the number of pharmacophore points fulfilled and their antagonistic potency. Some of these Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporationstructures are disclosed in the present work.Response to Reviewers: We sincerely appreciate the involvement of reviewer #1 and are deeply obliged. The reviewer was right in pointing the distortion of the ring and the amide in Figure 8 that has now been fixed in the revised version of Figure 8. We have also modified the viewpoint of Figure 9 to clearly show the protonation status of the terminal amine that was unfortunately hidden in the previous version of Figure 9 this study is summarized in a 3D pharmacophore that explains the observed structure-activity results and provides insight into the design of novel molecules with antagonistic profile. ...

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“…These data make the B 2 receptor an interesting model to study conformational changes associated to activation. In this respect the original nonpeptidic ligands designed by Fournier Research Laboratories, which constitute potential anti-inflammatory drugs (7,8), turned out to be interesting tools to modulate conformational equilibria. The purpose of the present work was to take advantage of constitutive activation phenomena to delineate some features of inactive receptor conformations and to propose a model of nonpeptide antagonist interaction with the B 2 receptor.…”

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confidence: 99%

Control of Conformational Equilibria in the Human B2 Bradykinin Receptor

Marie¹,

Richard²,

Pruneau³

et al. 2001

Journal of Biological Chemistry

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, receptor contact points with original nonpeptidic ligands. It provided an explanation for the ligand inverse agonist behavior on the WT receptor, with underlying restricted motions of TMs III, VI, and VII, and its agonist behavior on the Ala 113 and Phe 256 constitutively activated mutants. These data on the B 2 receptor emphasize that conformational equilibria are controlled in a coordinated fashion by key residues which are located at strategic positions for several G protein-coupled receptors. They are discussed in comparison with the recently determined rhodopsin crystallographic structure.

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LF 16.0335, a novel potent and selective nonpeptide antagonist of the human bradykinin B₂ receptor

Cited by 27 publications

References 46 publications

Sesamin Metabolites Induce an Endothelial Nitric Oxide-Dependent Vasorelaxation through Their Antioxidative Property-Independent Mechanisms: Possible Involvement of the Metabolites in the Antihypertensive Effect of Sesamin

Sesamin Metabolites Induce an Endothelial Nitric Oxide-Dependent Vasorelaxation through Their Antioxidative Property-Independent Mechanisms: Possible Involvement of the Metabolites in the Antihypertensive Effect of Sesamin

New insights into the stereochemical requirements of the bradykinin B1 receptor antagonists binding

Control of Conformational Equilibria in the Human B2 Bradykinin Receptor

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LF 16.0335, a novel potent and selective nonpeptide antagonist of the human bradykinin B2 receptor

Cited by 27 publications

References 46 publications

Sesamin Metabolites Induce an Endothelial Nitric Oxide-Dependent Vasorelaxation through Their Antioxidative Property-Independent Mechanisms: Possible Involvement of the Metabolites in the Antihypertensive Effect of Sesamin

Sesamin Metabolites Induce an Endothelial Nitric Oxide-Dependent Vasorelaxation through Their Antioxidative Property-Independent Mechanisms: Possible Involvement of the Metabolites in the Antihypertensive Effect of Sesamin

New insights into the stereochemical requirements of the bradykinin B1 receptor antagonists binding

Control of Conformational Equilibria in the Human B2 Bradykinin Receptor

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LF 16.0335, a novel potent and selective nonpeptide antagonist of the human bradykinin B₂ receptor