title: Constitutive receptor systems for drug discovery.
abstract: This paper discusses the use of constitutively active G-protein-coupled receptor systems for drug discovery. Specifically, the ternary complex model is used to define the two major theoretical advantages of constitutive receptor screening-namely, the ability to detect antagonists as well as agonists directly and the fact that constitutive systems are more sensitive to agonists. In experimental studies, transient transfection of Chinese hamster ovary cyclic AMP response element (CRE) luciferase reporter cells with cDNA for human parathyroid hormone receptor, glucagon receptor, and glucagon-like peptide (GLP-1) receptor showed cDNA concentration-dependent constitutive activity with parathyroid hormone (PTH-1) and glucagon. In contrast, no constitutive activity was observed for GLP-1 receptor, yet responses to GLP-1 indicated that receptor expression had taken place. In another functional system, Xenopus laevi melanophores transfected with cDNA for human calcitonin receptor showed constitutive activity. Nine ligands for the calcitonin receptor either increased or decreased constitutive activity in this assay. The sensitivity of the system to human calcitonin increased with increasing constitutive activity. These data indicate that, for those receptors which naturally produce constitutive activity, screening in this mode could be advantageous over other methods.
authors.affiliation: Department of Receptor Biochemistry, Glaxo Wellcome Research and Development, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.forename: C
authors.initials: C
authors.lastname: Jayawickreme
authors.forename: J
authors.initials: J
authors.lastname: Way
authors.forename: S
authors.initials: S
authors.lastname: Armour
authors.forename: K
authors.initials: K
authors.lastname: Queen
authors.forename: C
authors.initials: C
authors.lastname: Watson
authors.forename: D
authors.initials: D
authors.lastname: Ignar
authors.forename: W J
authors.initials: WJ
authors.lastname: Chen
authors.forename: T
authors.initials: T
authors.lastname: Kenakin
mesh_terms: D000818:Animals; D016466:CHO Cells; D002116:Calcitonin / Q000494:pharmacology; D006224:Cricetinae; D018076:DNA, Complementary / Q000235:genetics; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008547:Melanophores / Q000187:drug effects / Q000502:physiology; D008956:Models, Chemical; D008958:Models, Molecular; D018003:Receptors, Calcitonin / Q000187:drug effects / Q000235:genetics; D011955:Receptors, Drug / Q000737:chemistry*; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D018003:Receptors, Calcitonin; D011955:Receptors, Drug; D002116:Calcitonin