Functional Selectivity Of G Protein-coupled Receptor Ligands: New Opportunities For Drug Discovery (the Receptors)

Functional selectivity refers to the ability of different ligands acting at one receptor subtype to activate multiple signaling pathways in unique combinations; that is, one drug can be an agonist at pathway A and an antagonist or partial agonist at pathway B, and another drug can have the reverse profile. Functional selectivity has profound implications for drug development, for chemical biology, and for the design of experiments to characterize receptor function. In Functional Selectivity of G Protein-Coupled Receptors expert neuroscientists and pharmacologists review the work that demonstrated the existence of functional selectivity, placed it within a theoretical framework, and provided a mechanistic basis for the phenomenon. This exciting, comprehensive, and future-oriented volume includes chapters that focus on theoretical and mechanistic aspects of functional selectivity and that cut across subfamilies of GPCRs. Additional chapters focus on subfamilies of therapeutically relevant receptors where there is considerable evidence of ligand functional selectivity. Accessible and authoritative, Functional Selectivity of G Protein-Coupled Receptors is a valuable educational tool and reference source for students and scientists interested in drug development, chemical biology, and GPCR function. Doody Review Services Reviewer: Beth Levant, Ph.D.(University of Kansas Medical Center) Description: This book presents the current status of knowledge about ligand-specific intracellular signaling. Theoretical and mechanistic aspects of functional selectivity are presented first, followed by detailed chapters on specific therapeutically relevant receptors. Purpose: The purpose is to present what we currently know about ligand-specific intracellular signaling with a focus on its relevance to drug development. This is a relatively new and evolving field with numerous potential applications. The book does a commendable job of providing a theoretical background and summarizing the relevant literature for a number of specific receptors. Audience: This book will be of greatest interest and utility to scientists actively involved in research into G protein-coupled receptors or drug discovery. It is highly technical and assumes that the reader is familiar with receptor theory and G protein-coupled receptors specifically. The editor, a senior research career scientist at the Portland VA Medical Center and professor of behavioral neuroscience at Oregon Health & Science University, is an established authority on G protein-coupled receptors, particularly dopamine receptors. The chapter authors are authorities on their respective topics. Features: Six chapters on the theoretical and mechanistic aspects of functional selectivity begin the book. These are followed by chapters reviewing the primary literature supporting the existence of functional selectivity for adrenergic, muscarinic, serotonergic, dopaminergic, cannabinoid, opioid, and other peptide receptors; and the relevance of those findings to drug development. All chapters have extensive reference lists. High quality graphics aid understanding of the material. Assessment: This is a technically sophisticated, thorough, and detailed assessment of the current state of knowledge and recent developments in the field of G protein-coupled receptor function, signaling, and pharmacology. Functional selectivity refers to the ability of different ligands acting at one receptor subtype to activate multiple signaling pathways in unique combinations; that is, one drug can be an agonist at pathway A and an antagonist or partial agonist at pathway B, and another drug can have the reverse profile. Functional selectivity has profound implications for drug development, for chemical biology, and for the design of experiments to characterize receptor function. In Functional Selectivity of G Protein-Coupled Receptor Ligands, expert neuroscientists and pharmacologists reviewed the work that demonstrated the existence of functional selectivity, placed it within a theoretical framework, and provided a mechanistic basis for the phenomenon. This exciting, comprehensive, and future-oriented volume includes chapters that focus on theoretical and mechanistic aspects of functional selectivity and that cut across subfamilies of G protein-coupled receptors (GPCRs). Additional chapters focus on subfamilies of therapeutically relevant receptors where there is considerable evidence of ligand functional selectivity. Accessible and authoritative, Functional Selectivity of G Protein-Coupled Receptor Ligands is a valuable educational tool and reference source for students and scientists interested in drug development, chemical biology, and GPCR function Front Matter....Pages i-x Front Matter....Pages 1-1 Historical Overview of the Concept of Functional Selectivity....Pages 3-7 Functional Selectivity: Theoretical Considerations and Future Directions....Pages 9-24 Agonist-Selective Coupling of G Protein-Coupled Receptors....Pages 25-53 Ligand-Selective Receptor Desensitization and Endocytosis....Pages 55-69 Selectivity for G Protein or Arrestin-Mediated Signaling....Pages 71-85 In Vivo Evidence for and Consequences of Functional Selectivity....Pages 87-104 Front Matter....Pages 1-1 Functional Selectivity at Adrenergic Receptors....Pages 107-124 Signaling Diversity Mediated by Muscarinic Acetylcholine Receptor Subtypes and Evidence for Functional Selectivity....Pages 125-153 Functional Selectivity at Serotonin Receptors....Pages 155-176 Functional Selectivity at Dopamine Receptors....Pages 177-209 Functional Selectivity at Receptors for Cannabinoids and Other Lipids....Pages 211-241 Functional Selectivity at Opioid Receptors....Pages 243-265 Functional Selectivity at Non-Opioid Peptide Receptors....Pages 267-281 Back Matter....Pages 283-290