L-161,982 - CAS 147776-06-5
Category: Inhibitor
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Prostanoid Receptor
L-161,982 is a selective and potent EP4 receptor antagonist with Ki value of 0.024 µM. It is selective over all other members of the prostanoid receptor family with Ki values of 19, 23 and 1.90μM for human EP1, EP2 and EP3 receptors respectively. It suppresses PGE2-induced bone formation in young rats at 10 mg/kg/day and prevents the nociceptive response induced by misoprostol in formalin-injected mice. It reverses the anti-inflammatory action of PGE2 in LPS-activated human macrophages at 100 nM. It blocks PGE2-induced cell proliferation in HCA-7 colon cancer cells at 10 µM.
≥99% by HPLC
L-161,982; L 161,982; L161,982; N-[[4'-[[3-Butyl-1,5-dihydro-5-oxo-1-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-4-yl]methyl][1,1'-biphenyl]-2-yl]sulfonyl]-3-methyl-2-thiophenecarboxamide
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1.The anti-inflammatory effects of PGE
Gill SK;Yao Y;Kay LJ;Bewley MA;Marriott HM;Peachell PT Br J Pharmacol. 2016 Nov;173(21):3099-3109. doi: 10.1111/bph.13565. Epub 2016 Sep 6.
BACKGROUND AND PURPOSE: ;PGE;2; inhibits cytokine generation from human lung macrophages. However, the EP receptor that mediates this beneficial anti-inflammatory effect of PGE;2; has not been defined. The aim of this study was to identify the EP receptor by which PGE;2; inhibits cytokine generation from human lung macrophages. This was determined by using recently developed EP receptor ligands.;EXPERIMENTAL APPROACH: ;The effects of PGE;2; and EP-selective agonists on LPS-induced generation of TNF-α and IL-6 from macrophages were evaluated. The effects of EP;2; -selective (PF-04852946, PF-04418948) and EP;4; -selective (L-161,982, CJ-042794) receptor antagonists on PGE;2; responses were studied. The expression of EP receptor subtypes by human lung macrophages was determined by RT-PCR.;KEY RESULTS: ;PGE;2; inhibited LPS-induced and Streptococcus pneumoniae-induced cytokine generation from human lung macrophages. Analysis of mRNA levels indicated that macrophages expressed EP;2; and EP;4; receptors. L-902,688 (EP;4; receptor-selective agonist) was considerably more potent than butaprost (EP;2; receptor-selective agonist) as an inhibitor of TNF-α generation from macrophages. EP;2; receptor-selective antagonists had marginal effects on the PGE;2; inhibition of TNF-α generation, whereas EP;4; receptor-selective antagonists caused rightward shifts in the PGE;2; concentration-response curves.
2.Activation of intestinal Cl- secretion by lubiprostone requires the cystic fibrosis transmembrane conductance regulator.
Bijvelds MJ;Bot AG;Escher JC;De Jonge HR Gastroenterology. 2009 Sep;137(3):976-85. doi: 10.1053/j.gastro.2009.05.037. Epub 2009 May 18.
BACKGROUND & AIMS: ;Lubiprostone alleviates constipation by stimulating intestinal fluid secretion, purportedly through activation of ClC-2-type Cl(-) channels. Intestinal obstruction is also a recurrent cause of distress in cystic fibrosis (CF) patients, caused by loss of CF transmembrane conductance regulator (CFTR) Cl(-) channel activity. Because ClC-2 recruitment might be beneficial to CF patients, we investigated lubiprostone's mode of action.;METHODS: ;Cl(-) transport was measured in an Ussing chamber, in 3 model systems: (1) T84 colonocytes, (2) intestinal epithelium of wild-type and CF mice, and (3) intestinal epithelium of CF patients and controls.;RESULTS: ;In T84 monolayers, lubiprostone induced a robust secretory response. Selective permeabilization of the basolateral plasma membrane revealed that lubiprostone activated an apical Cl(-) conductance. The lubiprostone response was attenuated by H89, an inhibitor of the cAMP-dependent protein kinase, and lubiprostone precluded responsiveness to the cAMP agonist forskolin. CFTR blockage by CFTRinh172, but not ClC-2 blockage by CdCl(2), inhibited the lubiprostone response. Lubiprostone induced a CdCl(2)-insensitive secretory response in mouse intestine, but failed to induce intestinal Cl(-) secretion in Cftr-null mice.
3.Prostaglandin potentiates 5-HT responses in stomach and ileum innervating visceral afferent sensory neurons.
Kim S;Jin Z;Lee G;Park YS;Park CS;Jin YH Biochem Biophys Res Commun. 2015 Jan 2;456(1):167-72. doi: 10.1016/j.bbrc.2014.11.053. Epub 2014 Nov 22.
Gastrointestinal disorder is a common symptom induced by diverse pathophysiological conditions that include food tolerance, chemotherapy, and irradiation for therapy. Prostaglandin E2 (PGE2) level increase was often reported during gastrointestinal disorder and prostaglandin synthetase inhibitors has been used for ameliorate the symptoms. Exogenous administration of PGE2 induces gastrointestinal disorder, however, the mechanism of action is not known. Therefore, we tested PGE2 effect on visceral afferent sensory neurons of the rat. Interestingly, PGE2 itself did not evoked any response but enhanced serotonin (5-HT)-evoked currents up to 167% of the control level. The augmented 5-HT responses were completely inhibited by a 5-HT type 3 receptor antagonist, ondansetron. The PGE2-induced potentiation were blocked by a selective E-prostanoid type 4 (EP4) receptors antagonist, L-161,982, but type 1 and 2 receptor antagonist AH6809 has no effect. A membrane permeable protein kinase A (PKA) inhibitor, KT5720 also inhibited PGE2 effects. PGE2 induced 5-HT current augmentation was observed on 15% and 21% of the stomach and ileum projecting neurons, respectively. Current results suggest a synergistic signaling in visceral afferent neurons underlying gastrointestinal disorder involving PGE2 potentiation of 5-HT currents.
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CAS 147776-06-5 L-161,982

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