title: Synoptic pharmacology: Detecting and assessing the pharmacological significance of ligands for orphan receptors.
abstract: This paper discusses the discovery of ligands for orphan receptors and the identification of the natural endogenous ligands for those receptors in physiology. The central thesis is that orphan seven transmembrane receptors (7TMRs) are allosteric conduits of chemical information exchange from extracellular ligands to intracellar signaling mechanisms. This being the case, the optimal systems for discovery of orphan ligands must be synoptic in nature, that is, include the allosteric co-binding species that interact with the receptor since this latter component is essential for normal orphan 7TMR function. Constitutively active orphan receptor systems are also discussed as useful testing systems for orphan ligands. This is because the activated orphan receptor has a heightened sensitivity to cellular signaling species and thus whole cell constitutively active systems become sensitive to ligand binding. Finally, the phenomenon of biased signaling (due to stabilization of unique receptor active conformations) is discussed as a roadblock to the definitive identification of the natural orphan ligand but not to the detection of ligand tools to elucidate orphan 7TMR function.
authors.affiliation: Department of Pharmacology, University of North Carolina School of Medicine, 120 Mason Farm Road, Room 4042 Genetic Medicine Building, CB# 7365, Chapel Hill, NC 27599-7365, United States. Electronic address: kenakin@email.unc.edu.
authors.forename: Terry P
authors.initials: TP
authors.lastname: Kenakin
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D011487:Protein Conformation / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled
keywords: Constitutive; GPCRs; Orphan receptors; Receptors; Screening; activity