title: Identification of a potent and selective synthetic agonist at the CRTH2 receptor.
abstract: The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2) is a G protein-coupled receptor whose function in vivo has been incompletely characterized. One of the reasons is that its current known ligands, prostaglandin D(2) and some of its metabolites, have either poor selectivity for CRTH2 or are metabolically unstable in vivo. In this study, we describe the biological and pharmacological properties of L-888,607, the first synthetic potent and selective CRTH2 agonist. We show that L-888,607 exhibits 1) subnanomolar affinity for the human CRTH2 receptor, 2) high selectivity over all other prostanoid receptors and other receptors tested, 3) agonistic activity on recombinant and endogenously expressed CRTH2 receptor, and 4) relative stability in vivo. L-888,607 thus represents a suitable tool to investigate the in vivo function of CRTH2.
authors.affiliation: Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Quebec, Canada, H9H 3L1. francois_gervais@merck.com
authors.forename: François G
authors.initials: FG
authors.lastname: Gervais
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Morello
authors.forename: Christian
authors.initials: C
authors.lastname: Beaulieu
authors.forename: Nicole
authors.initials: N
authors.lastname: Sawyer
authors.forename: Danielle
authors.initials: D
authors.lastname: Denis
authors.forename: Gillian
authors.initials: G
authors.lastname: Greig
authors.forename: A Daniel
authors.initials: AD
authors.lastname: Malebranche
authors.forename: Gary P
authors.initials: GP
authors.lastname: O'Neill
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007213:Indomethacin / Q000031:analogs & derivatives / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011971:Receptors, Immunologic / Q000819:agonists* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000378:metabolism
chemical_list: C501945:(9-((4-chlorophenyl)thio)-6-fluoro-2,3-dihydro-1H-pyrrolo(1,2-a)indol-1-yl)acetic acid; D000085:Acetates; D006575:Heterocyclic Compounds, 3-Ring; D008024:Ligands; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D007213:Indomethacin; C036293:prostaglandin D2 receptor