TY - JOUR T1 - SR146131: A New Potent, Orally Active, and Selective Nonpeptide Cholecystokinin Subtype 1 Receptor Agonist. I: In Vitro Studies JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 742 LP - 751 VL - 289 IS - 2 AU - Eric Bignon AU - André Bachy AU - Robert Boigegrain AU - Roger Brodin AU - Michèle Cottineau AU - Danielle Gully AU - Jean-Marc Herbert AU - Peter Keane AU - Christophe Labie AU - Jean-Charles Molimard AU - Dominique Olliero AU - Florence Oury-Donat AU - Christophe Petereau AU - Valérie Prabonnaud AU - Marie-Pierre Rockstroh AU - Paul Schaeffer AU - Orlane Servant AU - Olivier Thurneyssen AU - Philippe Soubrié AU - Marc Pascal AU - Jean-Pierre Maffrand AU - Gérard Le Fur Y1 - 1999/05/01 UR - http://jpet.aspetjournals.org/content/289/2/742.abstract N2 - SR146131 inhibited the binding of [125I]-Bolton Hunter (BH)-sulfated cholecystokinin octapeptide (CCK-8S) for the human recombinant cholecystokinin subtype 1 (CCK1) receptor (IC50 = 0.56 nM) with high (300-fold) selectivity to the CCK2 receptor. The biological activity of SR146131 was characterized in vitro in a NIH-3T3 cell line expressing the human recombinant CCK1 receptor (3T3-hCCK1). Measuring intracellular calcium release, SR146131 behaved as a full agonist with an efficacy comparable with that of CCK-8S (EC50 = 1.38 ± 0.06 nM). On individual cells, SR146131 induced, like CCK-8S, Ca2+ oscillations at subnanomolar concentrations and sustained responses at higher concentrations. Like CCK-8S, SR146131 also fully stimulated inositol monophosphate formation (EC50 = 18 ± 4 nM). SR146131 partially activated mitogen-activated protein kinase and enhanced the expression of the immediate early gene krox 24. In the human CHP212 and IMR32 neuroblastoma cell lines, which constitutively express the CCK1 receptor, SR146131 behaved as a partial agonist on intracellular calcium release and inositol monophosphate formation. All of these effects of SR146131 were inhibited by the CCK1 receptor antagonists SR27897B and devazepide, suggesting that the effects of SR146131 were entirely mediated by the CCK1 receptor. In contrast, high concentrations (>1 μM) of SR146131 had only minimal effects on CCK-8S-stimulated and unstimulated Chinese hamster ovary (CHO) cells expressing the human CCK2 receptor, indicating that SR146131 is functionally inactive on the CCK2receptor. In conclusion, these in vitro experiments show that SR146131 is a highly potent and selective agonist of the CCK1receptor. The American Society for Pharmacology and Experimental Therapeutics ER -