Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Novel analogs of antisauvagine-30 (aSvg-30), a specific antagonist for corticotropin-releasing factor (CRF) receptor, type 2 (CRF(2)), have been synthesized and characterized in vitro and in vivo. The N-terminal amino acid D-phenylalanine in aSvg-30 was replaced by a D-tyrosine residue for specific radioactive labeling with 123I. Additionally, Met(17) of aSvg-30 was substituted by norleucine and the N-terminus of the peptide was acetylated to increase in vivo metabolic stability. The aSvg-30 analogs were tested for their ability to displace [125I-Tyr(0)]Svg in binding experiments and to inhibit Svg-stimulated adenylate cyclase activity in human embryonic kidney (HEK) 293 cells, permanently transfected with cDNA coding for the human CRF(1) (hCRF(1)), hCRF(2alpha) and hCRF(2beta) receptor. Ac-[D-Tyr(11), His(12), Nle(17)Svg(11-40), named K31440, showed high specific binding to hCRF(2alpha) (K(i) = 1.48 +/- 0.34 nM) and hCRF(2beta) (K(i) = 2.05 +/- 0.61 nM) but not the hCRF(1) receptor (K(i) = 288 +/- 13 nM) and decreased Svg-stimulated cAMP activity in hCRF(2)-expressing cells in a similar fashion as aSvg-30. In biodistribution studies specific uptake of 123I-K31440 was detected after 1 h in small intestine of BALB/c nude mice. These data demonstrate that 123I-K31440 may serve as a useful tool to detect native CRF(2) receptors and elucidate their role in gastrointestinal disorders and diseases such as irritable bowel syndrome or cancer.
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PMID:Design, synthesis and pharmacological characterization of new highly selective CRF(2) antagonists: development of 123I-K31440 as a potential SPECT ligand. 1183 94

Activated polymorphonuclear leucocytes, which are accumulated in inflammatory lesions of inflammatory bowel disease, produce tissue destructive, oxygen derived free radicals and other inflammatory mediators. The PMN superoxide production elicited by formyl-methionyl-leucyl-phenylalanine or the complement split product 5a were compared in IBD and healthy volunteers. Significantly reduced superoxide production was found in PMNs from patients with Crohn's disease as compared to normal controls, when fMLP or CSa were used as stimulants (p < 0.001 and p < 0.01, respectively), whereas no differences were found when ulcerative colitis patients were compared to normal controls (p > 0.05). The enhanced oxygen derived free radical production previously reported in active IBD, and especially in CD intestinal lesions, may either be due to an accumulation of productive phagocytes or to a change of the inflammatory profile of these cells when migrating into intestinal lesions, possibly due to interaction with other mediators (e.g. adhesion molecules and interleukins).
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PMID:In vitro Superoxide Production by Peripheral Neutrophils from Patients with Inflammatory Bowel Disease. 1847 36

Ibodutant (MEN15596, [1-(2-phenyl-1R-[[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl]-ethylcarbamoyl)-cyclopentyl]-amide) is a tachykinin NK(2) receptor (NK(2)R) antagonist currently under phase II clinical trials for irritable bowel syndrome. This study focuses on the ibodutant pharmacodynamic profile at the human NK(2)R and compares it with two other antagonists, nepadutant (MEN11420, (cyclo-[[Asn(beta-D-GlcNAc)-Asp-Trp-Phe-Dpr-Leu]cyclo(2beta-5beta)]) and saredutant [SR48968, (S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide]. In functional experiments (phosphatidylinositol accumulation) in Chinese hamster ovary cells expressing the human NK(2)R, ibodutant potency measured toward concentration-response curves to neurokinin A as pK(B) was 10.6, and its antagonism mechanism was surmountable and competitive. In the same assay, antagonism equilibration and reversibility experiments of receptor blockade indicated that ibodutant quickly attains equilibrium and that reverts from receptor compartment in a slower manner. Kinetic properties of ibodutant were assessed through competitive binding kinetics experiments performed at [(3)H]nepadutant and [(3)H]saredutant binding sites. Determined K(on) and K(off) values indicated a fast association and slow dissociation rate of ibodutant at the different antagonist binding sites. Last, by radioligand binding experiments at some mutated human tachykinin NK(2)Rs, the amino acidic determinants crucial for the high affinity of ibodutant were identified at the transmembrane (TM) level: Cys167 in TM4; Ile202 and Tyr206 in TM5; Phe270, Tyr266, and Trp263 in TM6; and Tyr289 in TM7. These results indicated an extended antagonist binding pocket in the TM portion of the receptor, which is conceived crucial for TM3 and 6 arrangement and leads to G protein-coupled receptor activation. By combining this information and molecular modeling, the docking mode of ibodutant-human NK(2)R complex is proposed.
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PMID:Multifaceted approach to determine the antagonist molecular mechanism and interaction of ibodutant ([1-(2-phenyl-1R-[[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl]-ethylcarbamoyl)-cyclopentyl]-amide) at the human tachykinin NK2 receptor. 1921 28

Morphiceptin (Tyr-Pro-Phe-Pro-NH(2)), a tetrapeptide present in the enzymatic digest of bovine beta-casein, is a selective ligand of the mu-opioid receptor. In the present study, we describe the synthesis of a series of novel morphiceptin analogs modified in positions 1-3. Two of the obtained analogs, [Dmt(1), D-Ala(2), D-1-Nal(3)]morphiceptin and [Dmt(1), D-NMeAla(2), D-1-Nal(3)]morphiceptin (Dmt-2',6'-dimethyltyrosine and d-1-Nal-3-(1-naphthyl)-D-alanine)) displayed very high mu-receptor affinity, resistance to enzymatic degradation, and remarkable supraspinally mediated analgesia, as shown in the hot-plate test after intracerebroventricular but not intravenous administration, which indicated that they could not cross the blood-brain barrier. Therefore, these two analogs were further tested in vitro and in vivo towards their possible peripheral analgesic activity and inhibitory effect on gastrointestinal (GI) motility. We report that both peptides showed strong antinociceptive effect in the writhing test after intraperitoneal administration, inhibited smooth muscle contractility in vitro and GI motility in vivo. Taken together, these findings indicate that the novel morphiceptin analogs which induce peripheral, but not central antinociception, inhibit GI transit, and possess exceptional metabolic stability, may provide an interesting approach to the development of peripherally restricted agents for the treatment of GI motility disorders, such as diarrhea or diarrhea-predominant irritable bowel syndrome.
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PMID:Synthesis and biological evaluation of novel peripherally active morphiceptin analogs. 2043 97