Free Fatty Acid Receptors (Handbook of Experimental Pharmacology (236))

"This book highlights the important role free fatty acids (FFA) play as potential drug targets. While FFA have long been considered byproducts of cell metabolism, they are now recognized as ligands that regulate cell and tissue function via G-protein-coupled receptors. At least three receptors have been identified for which FFA appear to be the endogenous ligands"--Publisher's description Preface 6 Contents 8 Ligands at Free Fatty Acid Receptor 1 (GPR40) 10 1 Introduction 11 2 Natural Ligands 12 3 Synthetic Ligands 12 3.1 Agonists 12 3.2 Antagonists 16 3.3 Fluorescent Ligands 16 4 Structure-Activity Relationships 17 5 Crystal Structure of FFA1 with TAK-875 17 6 Biased Agonism of FFA1 Ligand 18 7 Clinical Trials 19 8 Conclusions 21 References 21 Ligands at the Free Fatty Acid Receptors 2/3 (GPR43/GPR41) 26 1 The Short-Chain Fatty Acid Receptors 27 2 How Do SCFAs Interact with FFA2 and FFA3? 28 3 Orthosteric Ligands 29 3.1 Orthosteric Agonist Ligands 29 3.2 Orthosteric Antagonist Ligands 33 4 Allosteric Regulators of FFA2 and FFA3 35 4.1 Allosteric Regulators of FFA2 35 4.2 Allosteric Regulators of FFA3 37 5 Conclusions 38 References 38 Pharmacological Tool Compounds for the Free Fatty Acid Receptor 4 (FFA4/GPR120) 42 1 Introduction 43 2 What Is a Good Tool Compound? 43 3 Controlling FFA1-Mediated Effects 46 4 Chemical Probes for Studies of FFA4 48 4.1 Carboxylic Acid Probes 48 4.1.1 Long-Chain Fatty Acids 48 4.1.2 GW9508 50 4.1.3 TUG-891 52 4.1.4 Metabolex Compounds 54 4.1.5 Merck cpdA 55 4.2 Sulfonamide Probes 55 4.2.1 GSK137647A 55 4.2.2 Cyclic Sulfonamides, Banyu cpd 2 and TUG-1197 56 4.3 Antagonists 57 4.3.1 AH 7614 57 5 Outlook 57 References 61 Application of GPCR Structures for Modelling of Free Fatty Acid Receptors 66 1 Introduction 67 2 Free Fatty Acid Receptor 1 69 2.1 X-Ray Crystallography of FFA1 69 2.2 Molecular Modelling of FFA1 71 2.3 Docking to the FFA1 Crystal Structure 72 3 Free Fatty Acid Receptor 2 74 4 Free Fatty Acid Receptor 3 77 5 Free Fatty Acid Receptor 4 (GPR120) 78 6 GPR84 80 7 Summary and Future Directions 82 References 83 Using Biosensors to Study Free Fatty Acid Receptor Pharmacology and Function 87 1 Introduction 88 2 GPCR Pharmacology and Function 88 2.1 GPCR Signal Transduction 89 2.2 Expanding Complexity in GPCR Signalling 89 3 Biosensor Technologies to Study GPCRs 90 3.1 Genetically Encoded Biosensor Technologies 90 3.1.1 Context-Sensitive Biosensors 92 3.1.2 RET-Based Biosensors 93 3.1.3 Fragment Complementation Biosensors 93 3.1.4 Fluorescent vs Bioluminescent-Based Technologies 94 3.2 Non-genetically Encoded Biosensors 94 3.2.1 Label-Free Biosensors 95 3.2.2 Antibodies as Biosensors 95 4 Biosensors to Study the FFA Receptors 96 4.1 Studying FFA Receptors with Genetically Encoded Biosensors 96 4.1.1 Ligand Binding Sensors 96 4.1.2 G Protein Sensors 97 4.1.3 Arrestin Sensors 99 4.2 Studying FFA Receptors with Non-genetically Encoded Biosensors 101 4.2.1 Label-Free Biosensors 102 4.2.2 Antibody Biosensors 103 5 Conclusions and Future Perspectives 103 References 104 Key Questions for Translation of FFA Receptors: From Pharmacology to Medicines 109 1 Introduction 110 2 Challenges in Identification and Development of Pharmacological Molecules for FFA Receptors 113 2.1 Endogenous Receptor Tone and Constitutive Receptor Activity 114 2.2 Identification of Potent, Selective Small-Molecule Agonists/Antagonists 115 2.3 Agonist Receptor Pharmacology and Tachyphylaxis 116 2.4 Establishing Precedence for Disease Association 117 3 FFA Receptors and Therapeutic Indications 119 3.1 Type 2 Diabetes 119 3.1.1 FFA1 for Diabetes Treatment 120 3.1.2 FFAR4 Agonists for Treatment of Metabolic Disease 122 3.1.3 FFA2 and FFA3 for Metabolic Disease 124 3.2 FFAs, Inflammatory Disease, and the GI Tract 126 3.3 Other Indications 127 3.3.1 Neuronal 128 3.3.2 Cancer 128 3.3.3 Pain 128 4 Recommendations and the Therapeutic Future for FFAs 129 References 130 Polymorphic Variation in FFA Receptors: Functions and Consequences 140 1 Introduction 141 2 Free Fatty Acid Receptors 142 3 Polymorphic Variation of Receptors for SCFAs 143 3.1 FFA3 Functions and Polymorphisms 144 3.2 FFA2 Functions and Polymorphisms 147 4 Polymorphic Variation of Receptors for LCFAs 149 4.1 FFA1 Functions and Polymorphisms 150 4.2 FFA4 Functions and Polymorphisms 152 5 Conclusions 154 References 155 The Role and Future of FFA1 as a Therapeutic Target 166 1 Introduction 167 2 Stimulus-Secretion Coupling in the beta Cell 168 3 FFA1 in the Control of Insulin Secretion 170 4 FFA1 Signaling in Other Tissues 171 5 Role of FFA1 in Metabolic Disorders 173 6 Preclinical FFA1 Pharmacology 174 7 Allosterism, Ligand Cooperativity, and Functional Selectivity at FFA1 176 8 Clinical Benefits of FFA1 Agonism 179 9 Concluding Remarks 180 References 180 Gut Hormone Regulation and Secretion via FFA1 and FFA4 188 1 Introduction 189 1.1 Gut Hormones Responsive to Fat Absorption 189 1.2 Generation of FFA in the Gut Lumen 191 2 FFA1 and FFA4 in the Regulation of Gut Hormone Secretion 192 2.1 Expression of FFA1 in the Gut 192 2.2 Expression of FFA4 in the Gut 193 2.3 Natural and Small Molecule Ligands for FFA1 and FFA4 193 2.4 Studies on FFA1 and FFA4 in Enteroendocrine Cell Lines 195 2.5 FFA1-Dependence of Gut Hormone Secretion in Primary Enteroendocrine Cells and Rodent Models 196 2.6 FFA4 Dependence of Gut Hormone Secretion in Primary Cultures and Rodent Models 198 2.7 Signalling Pathways Downstream of FFA Receptors in Primary Enteroendocrine Cells 199 3 How Do Ingested Lipids Access FFA Receptors on Enteroendocrine Cells? 199 4 FFA1 and FFA4 as Candidate Targets for Increasing Endogenous Gut Hormone Release in Humans 201 5 Concluding Remarks 202 References 204 FFA2 and FFA3 in Metabolic Regulation 211 1 Introduction 212 2 Basic Properties of FFA2 and FFA3 213 3 Expression of FFA2 and FFA3 213 4 Physiological and Pathophysiological Functions of FFA2 and FFA3 216 4.1 Immune Cells 216 4.2 Enteroendocrine Cells 217 4.3 Adipose Tissue and Body Weight Control 218 4.4 Pancreatic beta-Cells 219 4.5 Nervous System 221 5 Pharmacological Potential of FFA2 and FFA3 221 6 Conclusions 222 References 222 Anti-Inflammatory and Insulin-Sensitizing Effects of Free Fatty Acid Receptors 227 1 Introduction 228 2 GPR120-Mediated Anti-Inflammatory Mechanisms 229 3 GPR40-Mediated Anti-Inflammatory Mechanisms 231 4 GPR84-Mediated Anti-Inflammatory Mechanisms 232 5 SCFAs Regulate Inflammatory and Metabolic Responses 233 6 GPR43-Mediated Anti-Inflammatory Mechanisms 233 7 GPR41-Mediated Anti-Inflammatory Mechanisms 234 8 Conclusion 234 References 235 Free Fatty Acid Receptors and Cancer: From Nutrition to Pharmacology 238 1 Introduction 239 2 FFAR Subtypes 240 3 FFA1/GPR40 242 3.1 Overview of FFA1 242 3.2 FFA1 in Breast Cancer 242 3.3 FFA1 in Other Cancers 244 4 FFA4/GPR120 245 4.1 Overview of FFA4 245 4.2 FFA4 in Prostate Cancer 246 4.3 FFA4 in Breast Cancer 247 4.4 FFA4 in Other Cancers 247 5 FFA2/GPR43 248 5.1 Overview of FFA2 248 5.2 FFA2 in Cancer 248 6 FFA3/GPR41 250 6.1 Overview of FFA3 250 6.2 FFA3 in Cancer 250 7 Conclusions 250 References 252 Index 257 Front Matter....Pages i-viii Ligands at Free Fatty Acid Receptor 1 (GPR40)....Pages 1-16 Ligands at the Free Fatty Acid Receptors 2/3 (GPR43/GPR41)....Pages 17-32 Pharmacological Tool Compounds for the Free Fatty Acid Receptor 4 (FFA4/GPR120)....Pages 33-56 Application of GPCR Structures for Modelling of Free Fatty Acid Receptors....Pages 57-77 Using Biosensors to Study Free Fatty Acid Receptor Pharmacology and Function....Pages 79-100 Key Questions for Translation of FFA Receptors: From Pharmacology to Medicines....Pages 101-131 Polymorphic Variation in FFA Receptors: Functions and Consequences....Pages 133-158 The Role and Future of FFA1 as a Therapeutic Target....Pages 159-180 Gut Hormone Regulation and Secretion via FFA1 and FFA4....Pages 181-203 FFA2 and FFA3 in Metabolic Regulation....Pages 205-220 Anti-Inflammatory and Insulin-Sensitizing Effects of Free Fatty Acid Receptors....Pages 221-231 Free Fatty Acid Receptors and Cancer: From Nutrition to Pharmacology....Pages 233-251 Back Matter....Pages 253-254