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Identification of Surrogate Agonists and Antagonists for Orphan G-Protein-Coupled Receptor GPR139

Department of Pharmaceutical Discovery, Lexicon Pharmaceuticals, The Woodlands, Texas, lhu{at}lexpharma.com

Pauline M. Tang

Department of Pharmaceutical Discovery, Lexicon Pharmaceuticals, The Woodlands, Texas

Nima K. Eslahi

Department of Pharmaceutical Discovery, Lexicon Pharmaceuticals, The Woodlands, Texas

Tian Zhou

Department of Pharmaceutical Discovery, Lexicon Pharmaceuticals, The Woodlands, Texas

Joseph Barbosa

Department of Medicinal Chemistry, Lexicon Pharmaceuticals, Princeton, New Jersey

Qingyun Liu

Department of Pharmaceutical Discovery, Lexicon Pharmaceuticals, The Woodlands, Texas

GPR139 is an orphan G-protein-coupled receptor (GPCR) that is expressed nearly exclusively in the central nervous system and may play a role in the control of locomotor activity. The signal transduction pathway and pharmacological function of GPR139, however, are still controversial due to the lack of natural or synthetic ligands. The authors report the characterization of human GPR139 signaling pathway and identification of surrogate agonists and antagonists. In both transient and stable transfections of HEK293F cells, overexpression of GPR139 increased basal intracellular cAMP concentrations compared to control cells. Furthermore, forskolin and isoproterenol-stimulated cAMP responses were enhanced in GPR139-expressing cells, suggesting that GPR139 is predominantly coupled to G_s. The authors screened a large library of small molecules for compounds that increase cAMP levels in GPR139-expressing cells and identified a compound with GPR139 agonist activity. This compound increased cAMP production specifically in cells expressing GPR139 but not in cells expressing its highly homologous receptor GPR142. Furthermore, this compound did not induce calcium mobilization in GPR139 cells, indicating no G_q-mediated response. In addition, antagonist screening with the identified agonist yielded 2 classes of compounds as antagonists. The identification of surrogate agonists and antagonists of human GPR139 provides important tools for further study of this orphan GPCR. (Journal of Biomolecular Screening 2009:789-797)

Key Words: GPR139 • orphan GPCR • HTS • agonist and antagonist

This version was published on August 1, 2009

Journal of Biomolecular Screening, Vol. 14, No. 7, 789-797 (2009)
DOI: 10.1177/1087057109335744


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