title: Allostery and Biased Agonism at Class B G Protein-Coupled Receptors.
abstract: Class B G protein-coupled receptors (GPCRs) respond to paracrine or endocrine peptide hormones involved in control of bone homeostasis, glucose regulation, satiety, and gastro-intestinal function, as well as pain transmission. These receptors are targets for existing drugs that treat osteoporosis, hypercalcaemia, Paget's disease, type II diabetes, and obesity and are being actively pursued as targets for numerous other diseases. Exploitation of class B receptors has been limited by difficulties with small molecule drug discovery and development and an under appreciation of factors governing optimal therapeutic efficacy. Recently, there has been increasing awareness of novel attributes of GPCR function that offer new opportunity for drug development. These include the presence of allosteric binding sites on the receptor that can be exploited as drug binding pockets and the ability of individual drugs to enrich subpopulations of receptor conformations to selectively control signaling, a phenomenon termed biased agonism. In this review, current knowledge of biased signaling and small molecule allostery within class B GPCRs is discussed, highlighting areas that have progressed significantly over the past decade, in addition to those that remain largely unexplored with respect to these phenomena.
authors.affiliation: Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville 3052, Victoria, Australia.
authors.forename: Denise
authors.initials: D
authors.lastname: Wootten
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic , Scottsdale, Arizona 85259, United States.
authors.forename: Laurence J
authors.initials: LJ
authors.lastname: Miller
authors.affiliation: Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville 3052, Victoria, Australia.|Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University , New York, New York 10065, United States.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Koole
authors.affiliation: Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville 3052, Victoria, Australia.
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.affiliation: Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville 3052, Victoria, Australia.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
mesh_terms: D000494:Allosteric Regulation; D019281:Dimerization; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D043562:Receptors, G-Protein-Coupled