Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pharmacological properties of the cyclic peptide Phe-cyclo[Lys-Tyr(3-tBu)-beta Ala-].trifluoroacetate (GM-109), a selective motilin antagonist, were investigated in the smooth muscle of the rabbit small intestine. GM-109 (0.1-3 microM) competitively inhibited contractions induced by porcine motilin (pMTL) in rabbit isolated duodenum longitudinal strips, with a pA2 value of 7.37 +/- 0.24. However, the contractile response to acetylcholine, to substance P, to prostaglandin F2 alpha and to KCl was unaffected by 10 microM GM-109 in the same preparation. Both GM-109 and pMTL competitively inhibited 125I-pMTL binding to motilin receptors in a homogenate of the rabbit small intestinal smooth muscle tissue. The pKi value of GM-109 and the pKd value of unlabeled pMTL were 7.99 +/- 0.04 and 9.25 +/- 0.06 (each n = 5), respectively. These results indicate that GM-109 is a selective and competitive motilin receptor antagonist in the smooth muscle of the rabbit small intestine. Thus this compound may be a useful pharmacological tool for examining the functional role(s) of motilin.
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PMID:GM-109: a novel, selective motilin receptor antagonist in the smooth muscle of the rabbit small intestine. 775 63

We describe the antagonistic properties due to the replacement of Pro3 by phenylalanine in porcine motilin. The analogue, [Phe3,Leu13] porcine motilin (OHM-11526), displaces iodinated [Nle13]porcine motilin bound to a homogenate of rabbit antral smooth muscle tissue. The dissociation constant (pKd) was 9.26 +/- 0.04, versus 9.11 +/- 0.01 for motilin and 8.24 +/- 0.06 for ANQ-11125, the (1-14) fragment of OHM-11526. The Hill coefficient was close to one and Schild plot analysis confirmed the competitive nature of the interaction. In the tissue bath OHM-11526 was unable to induce contractions of segments of rabbit duodenum. At a concentration of 10(-6) M, OHM-11526 was unable to induce contractions of segments of rabbit duodenum. At a concentration of 10(-6) M, OHM-11526 inhibited the effect of maximally effective doses of porcine motilin and of the erythromycin derivative, EM-523, but was without effect on contractions induced by acetylcholine, substance P and serotonin. Increasing doses of OHM-11526 shifted the dose-response curves of motilin and EM-523 to the right, but caused a depression of the maximal response as well. From the motilin curves, and assuming a dual competitive and non-competitive interaction, the pA2 was 7.79 +/- 0.08, the pD'2 6.91 +/- 0.08. The EM-523 curves yielded comparable data (pA2 = 8.10 +/- 0.12 and pD'2 = 7.06 +/- 0.13). OHM-11526 also blocked the motilin responses observed with smooth muscle strips from the rabbit and human antrum. However, in a preparation of the chicken small intestine, OHM-11526 was a full agonist with a potency (pD2 = 6.84) comparable to that of porcine motilin (pD2 = 6.71). Our data confirm the interaction of motilides with the motilin receptor. Due to its increased affinity for the motilin receptor, OHM-11526 will be a valuable took for studying the physiology of motilin and the pharmacology of motilin and motilides.
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PMID:Antagonistic properties of [Phe3,Leu13]porcine motilin. 860 85

Ghrelin is a GH-releasing peptide that also has an important role as an orexigenic hormone-stimulating food intake. By measuring inositol phosphate turnover or by using a reporter assay for transcriptional activity controlled by cAMP-responsive elements, the ghrelin receptor showed strong, ligand-independent signaling in transfected COS-7 or human embryonic kidney 293 cells. Ghrelin and a number of the known nonpeptide GH secretagogues acted as agonists stimulating inositol phosphate turnover further. In contrast, the low potency ghrelin antagonist, [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P was surprisingly found to be a high potency (EC50 = 5.2 nm) full inverse agonist as it decreased the constitutive signaling of the ghrelin receptor down to that observed in untransfected cells. The homologous motilin receptor functioned as a negative control as it did not display any sign of constitutive activity; however, upon agonist stimulation the motilin receptor signaled as strongly as the unstimulated ghrelin receptor. It is concluded that the ghrelin receptor is highly constitutively active and that this activity could be of physiological importance in its role as a regulator of both GH secretion and appetite control. It is suggested that inverse agonists for the ghrelin receptor could be particularly interesting for the treatment of obesity.
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PMID:High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist. 1290 57

The pharmacological properties of MA-2029, a novel motilin receptor antagonist, were investigated. In vitro, MA-2029 (1 to 30 nM) competitively inhibited motilin-induced contractions in isolated rabbit duodenal longitudinal muscle strips, with a pA2 value of 9.17+/-0.01 (n=5). However, contractile responses to acetylcholine and substance P were unaffected even at 1 microM of MA-2029. MA-2029 concentration-dependently inhibited the binding of [125 I]motilin to motilin receptors in a homogenate of rabbit colon smooth muscle tissue and membranes of HEK 293 cells expressing human motilin receptors. The pKi of MA-2029 was 8.58+/-0.04 in the rabbit colon homogenate (n=4) and 8.39 in the HEK 293 cells (mean of duplicate experiments). In vivo, orally-administered MA-2029 (3 to 30 mg/kg) dose-dependently inhibited colonic contractions induced by motilin (3 microg/kg, i.v.) in conscious rabbits. Inhibition was caused by all doses at 30 min after administration and by 10 mg/kg or more at 4 h after administration. The plasma concentration of MA-2029 correlated with its inhibitory effect. Furthermore, the oral administration of MA-2029 (0.3 to 3 mg/kg) also inhibited abdominal muscle contractions (an index of the visceral pain) induced by intravenous infusion of motilin (3 microg/kg/h) during colorectal distension in conscious rabbits. These results indicate that MA-2029 is an orally active, selective and competitive motilin receptor antagonist. It is suggested that this compound may be useful for gastrointestinal disorders associated with disturbed gastrointestinal motility such as irritable bowel syndrome.
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PMID:Oral administration of MA-2029, a novel selective and competitive motilin receptor antagonist, inhibits motilin-induced intestinal contractions and visceral pain in rabbits. 1816 86