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 tridecapeptide neurotensin (NT) contracts the guinea pig ileum through a neurogenic process that is mediated in part by acetylcholine and substance P and relaxes the guinea pig colon through a direct action on smooth muscle cells involving the opening of Ca(++)-dependent K+ channels. The non-peptide NT antagonist, SR 48692 (2-[1-(7-chloro-4-quinolinyl)-5-(2,6- dimethoxyphenyl)pyrazol-3-yl)carbonylamino]tricyclo-(3.3.1.1 .3.7)decan-2- carboxylic acid), potently inhibited NT binding to membranes prepared from the guinea pig ileum and colon with Ki values of approximately 3 nM. SR 48527 ((S)-(+)-[1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)pyrazol-3- yl)carbonylamino]cyclohexylacetic acid) and SR 49711 ((R)-(-)-[1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)pyrazol- 3-yl)carbonylamino]cyclohexylacetic acid), two enantiomers structurally related to SR 48692, were respectively equipotent with and a 100-fold less potent than SR 48692 in inhibiting NT binding in both tissues. In both membrane preparations, NT binding was increased by Mg++ and decreased by Na+ and guanosine 5'-[gamma-thio]triphosphate, whereas SR 48692 binding was not significantly affected by these agents. SR 48692 inhibited NT-induced contraction and relaxation in guinea pig ileum and colon preparations, respectively, with Ki values between 4 and 5 nM. As in binding studies, SR 48527 was as potent, whereas SR 49711 was 100-fold less potent than SR 48692 in antagonizing NT responses in both the guinea pig ileum and colon. Altogether, our results show that NT receptors in the guinea pig ileum and colon, although functionally distinct, are coupled to G-proteins and display similar biochemical and pharmacological properties, in particular with regard to their sensitivity and stereoselectivity toward nonpeptide antagonists related to SR 48692. Because of their high potency to antagonize NT actions in intestinal preparations, SR 48692 and SR 48527 represent useful tools to study the physiological role of NT in the digestive tract.
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PMID:Effect of the nonpeptide neurotensin antagonist, SR 48692, and two enantiomeric analogs, SR 48527 and SR 49711, on neurotensin binding and contractile responses in guinea pig ileum and colon. 796 24

Neurotensin reduced substance P-induced tension in ileal muscle strips and the relaxant effect was inhibited by a nonpeptide antagonist, SR 48692, 2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)pyrazol-3-yl)car bonylamino]tricyclo(3.3.1.1.(3.7)decan-2-carboxylic acid with a half-maximal concentration (IC50) of 7.4+/-2.1 nM (n = 9) and a dissociation constant (Kb) of 0.9+/-0.2 nM. Neurotensin produced a contractile response in ileal muscle strips pretreated with apamin (50 nM) and in isolated chick rectums and both contractile effects were inhibited by SR 48692 with IC50 of 31.6+/-9.5 nM and Kh of 3.2+/-0.9 nM (n = 6) and with IC50 of 28.9+/-6.9 nM and Kb of 5.4+/-1.0 nM (n = 7), respectively. The Kb values for the contractile effects were not significantly different from each other, but significantly different from that for the relaxant effect, suggesting that both types of effect are mediated via distinct subtypes of neurotensin receptor in the intestinal smooth muscles. Contractile responses and excitatory junction potentials evoked by electrical stimulation of nonadrenergic, noncholinergic (NANC) nerves in isolated chick rectums were not inhibited by SR 48692 (up to 3.3 microM). This does not provide functional evidence for the idea that neurotensin acts as an unidentified excitatory neurotransmitter of NANC nerves in the avian rectum.
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PMID:Characterization of neurotensin receptors in intestinal smooth muscle using a nonpeptide antagonist. 1020 84