GPCR Molecular Pharmacology and Drug Targeting E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1046

Veröffentlichungsjahr: 2010

Beschreibung

G protein-coupled receptors (GPCRs) are a large protein family of transmembrane receptors vital in dictating cellular responses. GPCRs are involved in many diseases, but are also the target of around half of all modern medicinal drugs.  Shifting Paradigms in G Protein Coupled Receptors takes a look at the way GPCRs are examined today, how they react, how their mutations lead to disease, and the many ways in which they can be screened for compounds that modulate them. Chemists, pharmacologists, and biologists will find essential information in this comprehensive reference.

Leseprobe

Table of Contents

Cover

Table of Contents

Half title page

Title page

Copyright page

Dedication

PREFACE

CONTRIBUTORS

CHAPTER 1 The Evolution of Receptors: From On–Off Switches to Microprocessors

1.1. INTRODUCTION

1.2. THE RECEPTOR AS AN ON–OFF SWITCH

1.3. HISTORICAL BACKGROUND AND CLASSICAL RECEPTOR THEORY

1.4. THE OPERATIONAL MODEL OF DRUG ACTION

1.5. RECEPTOR ANTAGONISM

1.6. SPECIFIC MODELS OF GPCRs (7TM RECEPTORS)

1.7. THE RECEPTOR AS MICROPROCESSOR: TERNARY COMPLEX MODELS

1.8. RECEPTORS AS BASIC DRUG RECOGNITION UNITS

1.9. RECEPTOR STRUCTURE

1.10. FUTURE CONSIDERATIONS

CHAPTER 2 The Evolving Pharmacology of GPCRs

2.1. AGONISTS, NEUTRAL ANTAGONISTS, AND INVERSE AGONISTS

2.2. LDTRS/PROTEAN AGONISM

2.3. MOLECULAR MECHANISMS OF GPCR LIGAND BINDING

2.4. TWO GPCR LIGANDS BINDING AT ONCE— CONCEPT OF ALLOSTERISM

2.5. GPCR DIMERIZATION

2.6. FUTURE PERSPECTIVES

ACKNOWLEDGMENTS

CHAPTER 3 The Emergence of Allosteric Modulators for G Protein-Coupled Receptors

3.1. INTRODUCTION

3.2. FOUNDATIONS OF ALLOSTERIC RECEPTOR THEORY

3.3. MODELS FOR UNDERSTANDING THE EFFECTS OF ALLOSTERIC MODULATORS

3.4. TYPES OF ALLOSTERIC MODULATORS AND THEIR PROPERTIES

3.5. DETECTION AND QUANTIFICATION OF ALLOSTERIC INTERACTIONS

3.6. SOME EXAMPLES OF GPCR ALLOSTERIC MODULATORS

3.7. CONCLUDING REMARKS

CHAPTER 4 Receptor-Mediated G Protein Activation: How, How Many, and Where?

4.1. THE MECHANICAL PROBLEM—THREE DIFFERENT SOLUTIONS

4.2. RECEPTOR MONOMERS–DIMERS–OLIGOMERS: ONE SIZE FITS ALL?

4.3. CORRALS, FENCES, RAFTS—ARE THERE PRIVILEGED PLACES FOR GPCR ACTIVATION?

ACKNOWLEDGMENTS

CHAPTER 5 Molecular Pharmacology of Frizzleds—with Implications for Possible Therapy

5.1. INTRODUCTION

5.2. FRIZZLEDS AS WNT RECEPTORS

5.3. FRIZZLED SIGNALING

5.4. FRIZZLEDS—PHYSIOLOGY AND POSSIBLE THERAPY

ACKNOWLEDGMENTS

CHAPTER 6 Secretin Receptor Dimerization: A Possible Functionally Important Paradigm for Family B G Protein-Coupled Receptors

6.1. METHODOLOGICAL APPROACHES TO GPCR OLIGOMERIZATION

6.2. STRUCTURAL THEMES FOR GPCR OLIGOMERIZATION

6.3. FUNCTIONAL EFFECTS OF GPCR OLIGOMERIZATION

6.4. SECRETIN RECEPTOR OLIGOMERIZATION

CHAPTER 7 Past and Future Strategies for GPCR Deorphanization

7.1. INTRODUCTION

7.2. CURRENT STRATEGIES TO IDENTIFY THE LIGAND AND FUNCTION OF ORPHAN 7TM PROTEINS

7.3. FUNCTIONAL ASSAYS FOR DEORPHANIZATION

7.4. FUTURE DIRECTIONS AND NEW CONCEPTS

7.5. CONTROVERSIAL ISSUES

ACKNOWLEDGMENTS

CHAPTER 8 High-Throughput GPCR Screening Technologies and the Emerging Importance of the Cell Phenotype

8.1. INTRODUCTION

8.2. HOW ARE GPCR DRUGS DISCOVERED?

8.3. GPCR DEPENDENCE ON G PROTEINS

8.4. TECHNOLOGIES FOR GPCR COMPOUND SCREENING AND DRUG DISCOVERY

8.5. IMPORTANCE OF TARGET CELLS IN GPCR HTS ASSAYS

8.6. SUMMARY

CHAPTER 9 Are “Traditional” Biochemical Techniques Out of Fashion in the New Era of GPCR Pharmacology?

9.1. OVERVIEW

9.2. RECEPTOR BINDING ASSAYS

9.3. METHODS FOR MEASUREMENT OF cAMP

9.4. CONCLUSIONS

CHAPTER 10 Fluorescence and Resonance Energy Transfer Shine New Light on GPCR Function

10.1. OVERVIEW

10.2. INTRODUCTION

10.3. LABELING GPCRs WITH FLUORESCENT TAGS

10.4. DETECTION OF FLUORESCENCE AND BIOLUMINESCENCE

10.5. FLUORESCENCE-BASED ASSAYS TO STUDY RECEPTOR LOCALIZATION, TRAFFICKING AND RECEPTOR FUNCTION

10.6. RESONANCE ENERGY TRANSFER, A TOOL TO GET NEW INSIGHTS INTO GPCR FUNCTION

10.7. ANALYSIS OF STEADY-STATE PROTEIN–PROTEIN INTERACTION BY MEANS OF RET

10.8. KINETIC ANALYSIS OF PROTEIN–PROTEIN INTERACTIONS BY MEANS OF FRET

10.9. DETECTION OF RECEPTOR FUNCTION BY FLUORESCENCE RESONANCE ENERGY

CHAPTER 11 Integration of Label-Free Detection Methods in GPCR Drug Discovery

11.1. OVERVIEW

11.2. INTRODUCTION

11.3. LABEL-FREE TECHNOLOGIES—PAST AND PRESENT

11.4. DISCUSSION

ACKNOWLEDGMENTS

CHAPTER 12 Screening for Allosteric Modulators of G Protein-Coupled Receptors

12.1. INTRODUCTION

12.2. THE ALLOSTERIC TERNARY COMPLEX MODEL, RADIOLIGAND BINDING, AND AFFINITY

12.3. BEYOND AFFINITY—FUNCTIONAL ASSAYS, EFFICACY, AND ALLOSTERIC AGONISM

12.4. ALLOSTERIC MODULATOR TITRATION CURVES

12.5. THE IMPACT OF FUNCTIONAL ASSAY FORMAT ON ALLOSTERIC MODULATOR SCREENING

12.6. TAKING ADVANTAGE OF STRUCTURAL UNDERSTANDING OF ALLOSTERIC BINDING SITES

12.7. SUMMARY AND FUTURE DIRECTIONS

CHAPTER 13 Ultra-High-Throughput Screening Assays for GPCRs

13.1. INTRODUCTION

13.2. ASSAY TYPES FOR GPCRs IN uHTS

13.3. SUMMARY

ACKNOWLEDGMENTS

CHAPTER 14 New Techniques to Express and Crystallize G Protein-Coupled Receptors

14.1. INTRODUCTION

14.2. KEY PROBLEMS LIMITING PRODUCTION OF 3D GPCR STRUCTURES

14.3. HISTORY OF GPCR STRUCTURES

14.4. THE SEARCH FOR OTHER GPCR STRUCTURES

14.5. PROTEIN PURIFICATION AND SOLUBILIZATION

14.6. IN CUBO CRYSTALLIZATION

14.7. ENGINEERING RECEPTOR STABILITY

14.8. STRUCTURES OF THE β2AR

14.9. THE ADENOSINE A2a RECEPTOR

14.10. CONCLUSIONS AND FUTURE DEVELOPMENTS

ACKNOWLEDGMENTS

CHAPTER 15 Structure and Modeling of GPCRs: Implications for Drug Discovery

15.1. INTRODUCTION

15.2. HIGH-RESOLUTION GPCR MODELING

15.3. CONSTRUCTING AND EVALUATING HOMOLOGY MODELS OF OTHER RECEPTOR TYPES

15.4. MODELING GPCR FUNCTIONAL FEATURES—ANALYSIS OF ACTIVATION AND SIGNALING

15.5. BEYOND CLASS A: MODELING OF OTHER GPCR FAMILIES

15.6. SUMMARY AND CONCLUSIONS

ACKNOWLEDGMENTS

CHAPTER 16 X-Ray Structure Developments for GPCR Drug Targets

16.1. OVERVIEW

16.2. INTRODUCTION

16.3. CLASS A GPCRs

16.4. CLASS C GPCRs

16.5. CONCLUSIONS

CHAPTER 17 Pharmacological Chaperones: Potential for the Treatment of Hereditary Diseases Caused by Mutations in G Protein-Coupled Receptors

17.1. OVERVIEW

17.2. INTRODUCTION

17.3. NDI AND THE V2R

17.4. RP AND THE RHODOPSIN RECEPTOR

17.5. IHH AND THE GONADOTROPIN-RELEASING HORMONE RECEPTOR

17.6. OTHER HUMAN DISEASES CAUSED BY INACTIVATING MUTATIONS IN GPCRs

17.7. CONSIDERATIONS FOR THE THERAPEUTIC USE OF PHARMACOLOGICAL CHAPERONES

17.8. CONCLUDING REMARKS

ACKNOWLEDGMENTS

Index

Color Plates

GPCR MOLECULAR PHARMACOLOGY AND DRUG TARGETING

Copyright © 2010 John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.

Published simultaneously in Canada.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, [phone], fax [phone], or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, [phone], fax [phone], or online at http://www.wiley.com/go/permission.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at [phone], outside the United States at [phone] or fax [phone].

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.

Library of Congress Cataloging-in-Publication Data:

GPCR molecular pharmacology and drug targeting : shifting paradigms and new directions / edited by Annette Gilchrist.

p. ; cm.

 Includes index.

 ISBN 978-0-470-30778-6 (cloth)

 ISBN 978-1-118-03517-7 (ebk)

 1. G proteins. 2. Drug targeting. I. Gilchrist, Annette.

 [DNLM: 1. Receptors, G-Protein-Coupled–physiology. 2. Drug Delivery Systems. 3. Molecular Structure. QV 38 G725 2010]

QP552.G16G627 2010

612′.015756–dc22

2009052133

To Josen and Finn, who arrived somewhere in the middle of all of this …

PREFACE

Although G protein-coupled receptors (GPCRs) have been the subject of study since the early days of pharmacology, our understanding of this large family of receptors continues to evolve. As a result, texts that discuss these receptors must constantly be rewritten and revised as emerging concepts are brought forth. Although many texts focus on GPCRs, none provide an overall look at the molecular pharmacology of this important target class. This book presents an up-to-date review on how scientists are thinking about GPCRs.

Early work includes the lock and key model of Fisher, and “receptive substances” to explain the biological actions of exogenous chemicals on cell “receptors,” and Clark’s occupancy theory that introduced the idea that the effect of an agonist is proportional to the number of occupied receptors. In the 1960s, the concept of intrinsic activity was introduced to explain the observation that not every agonist of a given receptor induced the same maximum effect. Compounds reaching the maximum were referred to as full agonist and other agonists were named partial agonist. This model was later extended to include drug efficacy and the system-independent concept of intrinsic efficacy. The mathematics applied in the models were relatively simple and allowed calculations to be made on affinity and activity. Looking back, it seems remarkable that most of these concepts were developed when little information on the biochemical nature of receptors or the underlying molecular mechanisms involved in signal transduction were available.

I have been working in the field of GPCRs for about 15 years, a time dwarfed by many of the contributing authors, who are well recognized as being experts in the field. In this time period, many of the basic pharmacology concepts for GPCRs have undergone radical changes. Yet, if one looks back, it seems that years before their general acceptance, there was research to support the paradigm shifts. For example, in 1989 Costa and Herz described antagonists with negative intrinsic activity at wild-type δ-opioid receptors (PNAS 1989 86: 7321-7325). Many subsequent studies have confirmed that GPCR proteins can signal in an agonist-independent, constitutive manner, and the concept of inverse agonism is now accepted and included in pharmacology textbooks. But in its early days, the concept of inverse agonism was hotly debated. Thus, the way we think about GPCRs, their basal activity, how they get activated, how they communicate the signal across the cell membrane, how they couple to each other as well as to other receptors and other membrane proteins, how their mutations lead to disease, and the many ways in which they can be screened for compounds that modulate them are constantly changing.

This textbook will serve as a resource for any scientists (e.g., pharmacologists, chemists, biologists) investigating GPCRs in both academia and industry (pharmaceutical/biotechnology). The book provides a general overview of GPCRs in terms of their biology and pharmacology, as well as recent developments including structure, deorphanization, dimerization, functional selectivity, and accessory proteins. In addition, it presents detailed methods on how to express, manipulate, and measure GPCRs. It is important to recognize that emerging concepts have shaped not only our understanding of GPCR pharmacology but also the drug discovery process itself. Recognition that most of the compounds initially considered to be competitive antagonists were inverse agonists, and studies indicating that the therapeutic outcome of inverse agonists and neutral antagonists can be different, led many companies to initiate drug discovery efforts specifically aimed at identifying inverse agonists. As a result, it is envisaged that this book on the shifting paradigms to GPCR pharmacology will be an essential resource for scientists working to identify compounds that selectively target members of this diverse family.

The book is organized into 17 chapters; the first seven chapters deal with the evolving pharmacology that surrounds this family, including chapters discussing allosteric modulators, receptor dimerization, GPCR deorphanization, G protein activation, and the Frizzled family. The next six chapters deal with methods to screen GPCRs, and include chapters on cell phenotype, “traditional” biochemical techniques, resonance energy transfer, label-free detection, and approaches for ultra-high-throughput screening. The next three chapters present GPCR structures, new ways to express and crystallize the receptors, as well as computational studies such as modeling and rational drug design. The final chapter describes the use of pharmacological chaperones for diseases caused by GPCR mutations.

ANNETTE GILCHRIST

Chicago College of Pharmacy

Midwestern University

CONTRIBUTORS

Ruben Abagyan, Bioinformatics and Systems Biology Graduate Program, University of California, La Jolla, CA

Elfrida R. Benjamin, Amicus Therapeutics, Cranbury, NJ

Magdalena Birker-Robaczewska, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland

Michel Bouvier, Département de Biochimie, Université de Montréal, Montréal, Quebec, Canada

Moritz Bünemann, Department of Pharmacology and Toxicology, Philipps-Universitaet Marburg, Marburg, Germany

Nathalie Clement, Institut Cochin, Université Paris Descartes, Department of Cell Biology, Paris, France

Arthur Christopoulos, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Victoria, Australia

Maria Teresa Dell’Anno, Department of Psychiatry, Neurobiology, Pharmacology and Biotechnologies, University of Pisa, Pisa, Italy

Maoqing Dong, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ

Richard M. Eglen, PerkinElmer Life and Analytical Sciences, Waltham, MA

James C. Errey, Heptares Therapeutics Limited, BioPark, Welwyn Garden City, Hertfordshire, UK

Michael Freissmuth, Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria

John Gatfield, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland

Karen J. Gregory, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Victoria, Australia

Christian W. Gruber, Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria

Ingrid Gsandtner, Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria

Kaleeckal G. Harikumar, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ

Stephen J. Hill, The University of Nottingham, Institute of Cell Signalling, School of Biomedical Sciences, Queen’s Medical Centre, Nottingham, UK

Carsten Hoffmann, Department of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany

Nicholas D. Holliday, The University of Nottingham, Institute of Cell Signalling, School of Biomedical Sciences, Queen’s Medical Centre, Nottingham, UK

Ralf Jockers, Institut Cochin, Université Paris Descartes, Department of Cell Biology, Paris, France

Vsevolod Katritch, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA

Terry Kenakin, Biochemical Reagents and Assay Development, GlaxoSmithKline Research and Development, Research Triangle Park, NC

Priya Kunapuli, In Vitro Sciences, External Discovery and Preclinical Sciences, Merck & Co., West Point, PA

Christopher Langmead, Heptares Therapeutics Limited, BioPark, Welwyn Garden City, UK

Angélique Levoye, Unité de Pathogénie Virale, Department of Virology, Institut Pasteur, Paris, France

Fiona H. Marshall, Heptares Therapeutics Limited, BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire, UK

Lauren T. May, The University of Nottingham, Institute of Cell Signalling, School of Biomedical Sciences, Queen’s Medical Centre, Nottingham, UK

Maria Rosa Mazzoni, Department of Psychiatry, Neurobiology, Pharmacology and Biotechnologies, University of Pisa, Pisa, Italy

Laurence J. Miller, Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic, Scottsdale, AZ

Oliver Nayler, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland

Terry Reisine, Independent Consultant, Los Angeles, CA

Patricia René, Département de Biochimie, Université de Montréal, Montréal, Quebec, Canada

Kimberly A. Reynolds, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX

Michael Sabio, Lundbeck Research USA, Paramus, NJ

Gunnar Schulte, Section of Receptor Biology and Signaling, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

Patrick M. Sexton, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Victoria, Australia

John Simms, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Victoria, Australia

Elodie Tenconi, Institut Cochin, Université Paris Descartes, Department of Cell Biology, Paris, France

Sidney W. Topiol, Lundbeck Research USA, Paramus, NJ

Celine Valant, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Victoria, Australia

Kenneth J. Valenzano, Amicus Therapeutics, Cranbury, NJ