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Journal of Biomolecular Screening
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Amphibian Melanophore Technology as a Functional Screen for Antagonists of G-Protein Coupled 7-Transmembrane Receptors

Mark E. Nuttall

Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA

John C. Lee

Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA

Paul R. Murdock

Gene Expression Sciences, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park (North), Harlow, Essex, United Kingdom

Alison M. Badger

Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA

Fei-Lan Wang

Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA

Jeffrey T. Laydon

Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA

Glenn A. Hofmann

Department of Biomolecular Discovery, SmithKline Beecham Pharmaceuticals, King of Prussia, PA

Gary R. Pettman

Microbial and Cell Culture Sciences, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park (North), Harlow, Essex, United Kingdom

Jonathan A. Lee

Department of Protein Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA

Ashu Parihar

NPS Pharmaceuticals, Salt Lake City, UT

Bradford C. Van Wagenen

NPS Pharmaceuticals, Salt Lake City, UT

John Fox

NPS Pharmaceuticals, Salt Lake City, UT

Maxine Gowen

Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA

Randall K. Johnson

Department of Oncology Research, SmithKline Beecham Pharmaceuticals, King of Prussia, PA

Michael R. Mattern

Department of Oncology Research, SmithKline Beecham Pharmaceuticals, King of Prussia, PA

Xenopus laevis melanophores stably expressing 7-transmembrane G-protein-coupled receptors were established and evaluated, either as a primary screening utility for antagonists of the human calcium receptor, or as a screen to assign function to binding inhibitors of human cannabinoid receptors. Stably or transiently expressing melanophores responded selectively to respective effectors of the human calcium, cannabinoid, and neurokinin-1 receptors. Several selective cannabinoid receptor-binding inhibitors of known potency were characterized as agonists or antagonists of the human peripheral cannabinoid (CB2) receptor. The results were consistent with changes in cAMP content of hCB2-transfected human embryonic kidney (HEK) cells challenged with the same CB2-binding antagonists. A stable melanophore cell line expressing the human calcium receptor was used to screen a compound collection directly for functional antagonists, several of which were confirmed as antagonists in secondary screens by stimulating parathyroid hormone (PTH) secretion from bovine parathyroid cells. The percentage of hits in this cell-based screen was reasonably low (1.2%), indicating minimal interference due to toxic effects and validating melanophores as a primary screening modality. Also described is the development of a novel procedure for cryopreservation and reconstitution of cells retaining functional human receptors.

Journal of Biomolecular Screening, Vol. 4, No. 5, 269-277 (1999)
DOI: 10.1177/108705719900400508
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