SR 48968, a neurokinin A (NK2) receptor antagonist

Emonds‐Alt, Xavier; Advenier, C.; Croci, Tiziano; Manara, L.; Néliat, Gervais; Poncelet, Marc; Proietto, Vincenzo; Santucci, Vincent; Soubrié, Philippe; Broeck, Didier Van; Vilain, P.; Fur, G. Le; Brelière, Jean-Claude

doi:10.1016/0167-0115(93)90008-v

Cited by 35 publications

(12 citation statements)

References 14 publications

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“…This would mean that several point mutations must be combined to seriously affect the binding of such compounds. Interestingly, small chemical modifications of SR140,333 create compounds that are high affinity, selective NK 2 or NK 3 ligands (Emonds-Alt et al, 1993a). For the homologous nonpeptide antagonist SR48,968, it has been reported that the combination of a couple of point substitutions is required to affect the binding of this compound, which is very similar structurally to the NK 2 receptor (Huang et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK₁Receptor

et al. 1998

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Residues in transmembrane domain (TM)-III, TM-V, TM-VI, and TM-VII believed to be facing the deep part of the presumed main ligand-binding pocket of the NK 1 receptor were probed by alanine substitution and introduction of residues with larger and/or chemically distinct side chains. Unaltered or even improved binding affinity for four peptide agonists, substance P, substance P-O-methyl ester, eledoisin, and neurokinin A, as well as normal EC 50 values for substance P in stimulating phosphatidylinositol turnover indicated that these mutations did not alter the overall functional integrity of the receptor. The alanine substitutions in general had only minor effects on nonpeptide antagonist binding. However, the introduction of the larger and polar aspartic acid and histidine residues at positions corresponding to the monoamine binding aspartic acid in TM-III of the ␤ 2 -adrenoceptor (ProIII:08, Pro112 in the NK 1 receptor) and to the presumed monoamine interacting "two serines" in TM-V (ThrV:09, Thr201; and IleV:12, Ile204) impaired by Ͼ100-fold the binding of a group of nonpeptide antagonists, including CP96,345, CP99,994, RP67,580, RPR100,893, and CAM4092. In contrast, another group of nonpeptide antagonists, LY303,870, FK888, and SR140,333, were little or not at all affected by the space-filling substitutions. Two of these compounds, FK888 and LY303,870, were those most seriously affected (75-89-fold) by alanine substitution of PheVI:20 located in the upper part of the main ligand-binding crevice.

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Section: Discussionmentioning

confidence: 99%

Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK₁Receptor

et al. 1998

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“…The actions of the tachykinins on intestinal effector systems are mediated via three distinct receptor subtypes, neurokinins 1, 2 and 3 (NK1, NK2 and NK3) [13], that can be distinguished using a variety of selective agonists and antagonists [14][15][16][17][18][19]. These receptor subtypes can be preferentially stimulated by the endogenous neuropeptides substance P, neurokinin A (NKA) and neurokinin B (NKB), respectively.…”

Section: Introductionmentioning

confidence: 99%

Chronic Inflammation Alters the Contribution of Neurokinin Receptor Subtypes to Epithelial Function in Rat Colon

2007

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We have previously shown that neurokinin-1 (NK1) receptors predominantly mediate substance P-induced secretion of the non-inflamed rat colonic mucosa in vitro with a gradient in the magnitude of these responses. The aim of this study was to examine the effects of chronic inflammation on the contributions of different neurokinin receptor subtypes to colonic mucosal secretion. Colitis was induced by the intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid in rats, reactivated 6 weeks later. Segments of proximal, mid- and distal colon were stripped of muscularis propria and mounted in Ussing chambers for measurement of short-circuit current. Use of selective agonists suggests that in the chronically inflamed rat colon NK1 receptors play a greater role in neurokinin-mediated mucosal secretion than do either NK2 or NK3. Selective antagonism implies that this is region-specific, with the inflammatory process altering the relative contribution of the neurokinin receptor subtypes within each region of the rat colon.

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“…The actions of the tachykinins on intestinal effector systems are mediated via three distinct receptor subtypes, NK1, NK2, and NK3 (7), which can be distinguished via the use of a variety of selective agonists and antagonists (8)(9)(10)(11)(12)(13). These receptors can be preferentially stimulated by the endogenous neuropeptides substance P, neurokinin A (NKA), and neurokinin B (NKB) respectively.…”

mentioning

confidence: 99%

Regional Variations in Neurokinin Receptor Subtype Contributions to Muscularis Mucosae and Epithelial Function in Rat Colon

2006

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It is known that the muscularis mucosae and mucosa are not pharmacologically homogeneous throughout the rat colon. The aim of this study was to simultaneously characterize all three neurokinin (NK) receptors in the muscularis mucosae and mucosa along the length of the rat colon. Strips of proximal, mid, and distal colonic muscularis mucosae were prepared for isometric recording or sheets of muscle-free mucosa were mounted in Ussing chambers for measurement of short-circuit current. In both muscularis mucosae and mucosa the greatest responses to substance P were found in the proximal region. Use of selective agonists revealed the presence of all three NK receptors in both structures, however, selective antagonism suggests that only NK2 receptors in the muscularis mucosae and NK1 receptors in the mucosa are physiologically relevant. In conclusion, substance P-induced responses in the rat colon are region-specific and not mediated by a single NK receptor subtype common to both structures.

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SR 48968, a neurokinin A (NK2) receptor antagonist

Cited by 35 publications

References 14 publications

Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK₁Receptor

Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK₁Receptor

Chronic Inflammation Alters the Contribution of Neurokinin Receptor Subtypes to Epithelial Function in Rat Colon

Regional Variations in Neurokinin Receptor Subtype Contributions to Muscularis Mucosae and Epithelial Function in Rat Colon

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SR 48968, a neurokinin A (NK2) receptor antagonist

Cited by 35 publications

References 14 publications

Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK1Receptor

Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK1Receptor

Chronic Inflammation Alters the Contribution of Neurokinin Receptor Subtypes to Epithelial Function in Rat Colon

Regional Variations in Neurokinin Receptor Subtype Contributions to Muscularis Mucosae and Epithelial Function in Rat Colon

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Product

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Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK₁Receptor

Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK₁Receptor