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First published on March 8, 2005; DOI: 10.1124/mol.104.009068

0026-895X/05/6706-1834-1839$20.00
Mol Pharmacol 67:1834-1839, 2005

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Identification of a Potent and Selective Synthetic Agonist at the CRTH2 Receptor

François G. Gervais, Jean-Pierre Morello, Christian Beaulieu, Nicole Sawyer, Danielle Denis, Gillian Greig, A. Daniel Malebranche, and Gary P. O'Neill

Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada

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 D2 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.

Received for publication November 9, 2004.

Accepted for publication February 16, 2005.

Address correspondence to: Dr. Francois G. Gervais, Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, QC, Canada, H9H 3L1. E-mail: francois_gervais{at}merck.com




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J. M. Mathiesen, T. Ulven, L. Martini, L. O. Gerlach, A. Heinemann, and E. Kostenis
Identification of Indole Derivatives Exclusively Interfering with a G Protein-Independent Signaling Pathway of the Prostaglandin D2 Receptor CRTH2
Mol. Pharmacol., August 1, 2005; 68(2): 393 - 402.
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