title: "Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology.
abstract: G-protein-coupled receptors (GPCRs) represent the largest class of drug targets, accounting for more than 40% of marketed drugs; however, discovery efforts for many GPCRs have failed to provide viable drug candidates. Historically, drug discovery efforts have focused on developing ligands that act at the orthosteric site of the endogenous agonist. Recently, efforts have focused on functional assay paradigms and the discovery of ligands that act at allosteric sites to modulate receptor function in either a positive, negative, or neutral manner. Allosteric modulators have numerous advantages over orthosteric ligands, including high subtype selectivity; the ability to mimic physiological conditions; the lack of densensitization, downregulation, and internalization; and reduced side effects. Despite these virtues, challenging issues have now arisen for allosteric modulators of metabotropic glutamate receptors (mGluRs): shallow SAR, ligand-directed trafficking, and the identification of subtle "molecular switches" that modulate the modes of pharmacology. Here, we will discuss the impact of modest structural changes to multiple mGluR allosteric ligands scaffolds that unexpectedly modulate pharmacology and raise concerns over metabolism and the pharmacology of metabolites.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
authors.forename: John T
authors.initials: JT
authors.lastname: Brogan
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D015195:Drug Design; D004347:Drug Interactions; D006801:Humans; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008024:Ligands; D018094:Receptors, Metabotropic Glutamate