THERAPEUTIC TARGETS: MODULATION, INHIBITION, AND ACTIVATION -- CONTENTS -- Preface -- Contributors -- 1. cAMP-Specific Phosphodiesterases: Modulation, Inhibition, and Activation -- 1.1 INTRODUCTION -- 1.2 GENERAL CHARACTERISTICS OF PHOSPHODIESTERASES SPECIFIC FOR CYCLIC ADENOSINE MONOPHOSPHATE -- 1.2.1 Modular Structure of cAMP-Specific PDEs -- 1.2.2 PDE4s: Characterization and Regulation -- Diversity of Isoforms -- N-Terminal "Anchor" -- UCR Regions -- C-Terminal Site -- Regulation of PDE4 Function by Posttranslation Modifications Other than Phosphorylation -- 1.2.3 Inhibition of PDE4 as a Therapeutic Strategy -- Pharmacologic Inhibition of the PDE4 Active Site -- Novel Allosteric PDE4 Inhibitors -- Alternative Strategies for Inhibition of Localized PDE4 Pools -- PDE4 Knockout Mice -- 1.2.4 PDE7 -- Characterization -- Expression -- Modulation -- Inhibition -- 1.2.5 PDE8 -- Characterization -- Expression -- Modulation -- Inhibition -- 1.3 CONCLUSIONS -- ACKNOWLEDGMENTS -- REFERENCES -- 2. Protease-Activated Receptor 2 -- 2.1 INTRODUCTION -- 2.2 OVERVIEW OF PAR2 -- 2.2.1 Activation -- 2.2.2 Signal Transduction of PAR2 -- 2.2.3 Termination of PAR2 Signal -- 2.3 PAR2 IN PHYSIOLOGY AND DISEASE -- 2.3.1 PAR2 in Inflammation and Pain -- 2.3.2 PAR2 in the Respiratory System -- 2.3.3 PAR2 in Cardiovascular System -- 2.3.4 PAR2 in the Gastrointestinal System -- 2.3.5 PAR2 and Cancer -- 2.3.6 PAR2 as a Therapeutic Target -- 2.4 CONCLUSION -- ACKNOWLEDGMENT -- REFERENCES -- 3. Voltage-Gated Sodium Channels as Therapeutic Targets -- 3.1 INTRODUCTION -- 3.2 INTRODUCTION TO VOLTAGE-GATED SODIUM CHANNELS -- 3.2.1 The Nav Family -- 3.2.2 Nav Channel Structure -- The α-Subunit Pore -- The Inactivation Gate -- Voltage Sensor -- 3.2.3 Protein-Protein Modulation of Nav Channels -- 3.2.4 β Subunits -- 3.2.5 Therapeutic Relevance of Nav Channels.

Pain and Inflammation -- Muscle Channelopathies (Nav1.4) -- Cardiac Arrhythmias (Nav1.5) -- Nav Channels and Epilepsy -- Migraine (Nav1.1) -- Cancer -- Multiple Sclerosis and Immunomodulation -- 3.3 Nav MODULATION WITH PEPTIDES AND SMALL MOLECULES -- 3.3.1 Site-Specific Modulation of Nav Channels -- Site 1: Pore Blockers -- Sites 2 and 5: Intracellular Voltage-Dependent Gating Modulators -- Sites 3 and 4: Extracellular Voltage-Dependent Gating Modulators -- Site 6 -- 3.4 NEW THERAPEUTIC DIRECTIONS FOR NaV CHANNEL DRUG DISCOVERY -- 3.4.1 Heterologous Expression of Nav -- 3.4.2 Assay Technologies -- Electrophysiology -- Challenges with Automated Electrophysiology Platforms -- Cell-Based Functional Assay -- Fluorescence-Based Assays -- Cytotoxicity Assays -- Binding Assays -- Ion Flux Assays -- 3.4.3 Label-Free Technology -- 3.4.4 Venoms as Potent/Selective Drug Leads -- 3.5 CONCLUSIONS -- REFERENCES -- 4. Multitarget Drugs for Stabilization of Calcium Cycling and Neuroprotection in Neurodegenerative Diseases and Stroke -- 4.1 INTRODUCTION -- 4.2 CALCIUM AS A UBIQUITOUS CELL MESSENGER -- 4.2.1 Evolution of the Concept of Calcium Signaling -- 4.2.2 Properties of Calcium that Make it an Ideal Cell Messenger -- 4.3 CALCIUM ENTRY INTO CELLS -- 4.3.1 Diversity of Voltage-Dependent Calcium Channels -- 4.3.2 Neurotransmitter-Activated Calcium Channels -- Calcium-Permeable Nicotinic Receptors -- Calcium-Permeable Glutamate Receptors -- 4.3.3 Store-Operated Calcium Channels -- 4.4 INTRACELLULAR CALCIUM MOVEMENT -- 4.4.1 Transport of Calcium by Sarcoplasmic and Endoplasmic Reticula -- 4.4.2 Mitochondrial Calcium Movement -- Mitochondrial Calcium Uptake -- Mitochondrial Calcium Efflux -- Mitochondrial Permeability Transition Pore -- Mitochondrial Calcium Cycling -- 4.4.3 Calcium Handling by Secretory Vesicles -- 4.4.4 Calcium Binding Proteins.

4.5 EFFLUX OF CALCIUM FROM CELLS -- 4.5.1 Plasmalemmal Calcium Pump -- 4.5.2 Plasmalemmal Sodium/Calcium Exchanger -- 4.6 CALCIUM CYCLING AND CALCIUM FUNCTIONS IN NEURONS -- 4.6.1 Calcium Signaling and Calcium Cycling in Neurons -- 4.6.2 Calcium Functions in Neurons -- 4.6.3 Calcium, Neuronal Viability, and Neuronal Death -- 4.7 CALCIUM DYSREGULATION IN ALZHEIMER'S DISEASE -- 4.8 CALCIUM DYSREGULATION IN AMYOTROPHIC LATERAL SCLEROSIS -- 4.8.1 Distortion of Calcium Entry through AMPA Receptors -- 4.8.2 Alteration of Cytosolic Calcium Signals Linked to Calcium Binding Protein Dysfunction -- 4.8.3 Mitochondrial Calcium Cycling and Selective Motor Neuron Vulnerability -- 4.8.4 The Link between Mitochondrial Calcium Cycling and the Production of Reactive-Oxygen Species -- 4.9 CALCIUM DYSREGULATION IN PARKINSON'S DISEASE -- 4.10 CALCIUM DYSREGULATION IN HUNTINGTON'S DISEASE -- 4.11 CALCIUM DYSREGULATION IN STROKE -- 4.12 THE CONCEPT OF MULTITARGET DRUG LIGANDS USED TO RESCUE FROM DEATH THE VULNERABLE NEURONS OF NEURODEGENERATIVE DISEASES AND STROKE -- 4.12.1 The Concept of Single-Target versus Multitarget Compounds in Drug Therapy -- 4.12.2 The Multitarget Drug Ligand Strategy for Neuroprotection -- 4.12.3 Multitarget Stabilizers of Neuronal Calcium Cycling -- 4.12.4 Regulation of Mitochondrial Calcium Cycling as a Strategy for Developing Novel Multitarget Neuroprotective Compounds -- 4.12.5 Stabilizers of Neuronal and Mitochondrial Calcium Cycling in Clinical Trials -- 4.13 CONCLUSIONS AND PERSPECTIVES -- REFERENCES -- 5. Oligomerization of G-Protein-Coupled Receptors -- 5.1 INTRODUCTION -- 5.2 GABAB RECEPTORS AS A PARADIGM OF FIRST FUNCTIONAL EVIDENCE OF GPCR HETEROMERIZATION -- 5.3 DETERMINING WHETHER ALL GPCRs ARE DIMERS: THE RHODOPSIN-RELATED FAMILY A RECEPTORS.

5.4 PHYSIOLOGICAL IMPLICATIONS OF GPCR HETEROMERIZATION: HETEROCOMPLEXES IN NEUROPSYCHIATRIC DISORDERS -- 5.5 RECOMMENDATIONS FOR THE RECOGNITION OF GPCR HETEROMULTIMERS -- 5.6 CONCLUDING REMARKS -- REFERENCES -- 6. Sigma 1 Receptor Chaperone: Pharmacology and Therapeutic Perspectives -- 6.1 INTRODUCTION TO THE TARGET AND STATE OF THE ART -- 6.1.1 σ1 Receptor: A Dynamic Modulatory Protein -- 6.1.2 σ1 Receptor as a Drug Target -- 6.2 DRUGS TARGETING σ1 RECEPTOR -- 6.2.1 Putative Endogenous Ligands for σ1 Receptor -- 6.2.2 Drug Development Activity of σ1 Receptor Ligands -- 6.2.3 σ1 Receptor Antagonists and Schizophrenia -- 6.2.4 σ1 Receptor Agonists and Depression -- 6.2.5 σ1 Receptor Agonists and Anxiety -- 6.3 THERAPEUTIC PERSPECTIVES FOR σ1 RECEPTOR LIGANDS -- 6.3.1 Neuroprotection -- 6.3.2 Drug Dependence -- 6.3.3 Cancer -- 6.3.4 Cardioprotection -- 6.3.5 Pain -- 6.4 CONCLUSIONS -- REFERENCES -- 7. Lipids as New Targets -- 7.1 INTRODUCTION -- 7.2 LIPID METABOLISM AND TRANSPORT -- 7.2.1 Lipid Breakdown -- 7.2.2 Lipid Biosynthesis -- 7.2.3 Lipid Transport -- 7.2.4 HDL Metabolism: Reverse Cholesterol Transport (RCT) -- 7.2.5 Lipoprotein Metabolism Regulation -- 7.3 LIPOPROTEINS AND DISEASE: DYSLIPIDEMIA, ATHEROSCLEROSIS, OBESITY, AND THE METABOLIC SYNDROME -- 7.4 CURRENT AND CANDIDATE TARGETS FOR LIPID METABOLISM REGULATION -- 7.4.1 Current Targets and Agents for Lipid Metabolism Regulation -- HMG-CoA) Reductase Inhibition: Statins -- Bile Acid Sequestrants -- Cholesterol Absorption Inhibitors -- GPR109A Agonists: Nicotinic Acid -- PPARα Agonism: Fibrates -- GPR120 and Other Agonists: ω3 Fatty Acids -- Pancreatic Lipase Inhibition: Orlistat -- 7.4.2 Candidate Targets and Agents for Lipid Metabolism Regulation -- Endocannabinoid Receptor Blockers -- Promotion of Reverse Cholesterol Transport.

Triacylglycerol Hydrolase/Carboxylesterase 3 (TGH/CES3) as a Candidate Target for Lowering Blood Lipid Levels -- Sortilin (SORT1) in Atherosclerosis -- Monoacylglycerol Lipase (MAGL) Inhibition in Cancer -- 7.5 NEW DISCOVERY TOOLS FOR LIPID METABOLISM REGULATION: LIPIDOMICS -- 7.6 CONCLUSIONS -- REFERENCES -- 8. Knowledge Base for Nuclear Receptor Drug Discovery -- 8.1 INTRODUCTION -- 8.2 CHEMICAL KNOWLEDGE BASE -- 8.3 STRUCTURAL KNOWLEDGE BASE -- 8.4 COMPLETING THE KNOWLEDGE BASE -- 8.5 DRUG SELECTIVITY -- 8.6 CONCLUSIONS -- REFERENCES -- 9. Gene Promoters and Transcription Control Regions as Therapeutic Targets -- 9.1 INTRODUCTION -- 9.2 TRANSCRIPTION CONTROL REGIONS IN PROTEIN CODING GENES -- 9.3 INDUCTION OF SPECIFIC GENES AS A THERAPEUTICALLY BENEFICIAL STRATEGY -- 9.4 REPRESSION OF SPECIFIC GENES AND THERAPEUTIC BENEFIT -- 9.5 DEVELOPMENT OF CELL-BASED REPORTER ASSAYS FOR SCREENING MODULATORS OF GENE PROMOTERS -- 9.5.1 Generation of Promoter-Reporter Gene Constructs -- Choice of Promoter -- Choice of Reporter -- 9.5.2 Generation and Validation of the Cellular Model -- 9.5.3 Optimization and Miniaturization of Conditions for Cell-Based Reporter Assay in HTS -- 9.5.4 Validation of HTS Screening -- 9.6 CONCLUSIONS AND FUTURE CHALLENGES IN THE SEARCH FOR MODULATORS OF GENE PROMOTERS AS DRUGS -- ACKNOWLEDGMENTS -- REFERENCES -- 10. Roles of Glucagon-Like Peptide and Glucose-Dependent Insolinotropic Polypeptide Hormones in Brain Function and Neurodegeneration -- 10.1 INTRODUCTION -- 10.2 A CAUSAL LINK BETWEEN DIABETES AND ALZHEIMER'S DISEASE -- 10.3 THE INCRETINS: GLUCAGON-LIKE PEPTIDE 1 AND GLUCOSE-DEPENDENT INSOLINOTROPIC POLYPEPTIDE -- 10.3.1 The Development of Longerlasting Incretin Analogs -- 10.3.2 Incretin Roles in the Brain -- 10.3.3 Incretin Analogs Crossing the Blood-Brain Barrier -- 10.3.4 Effects of Incretins on Synaptic Transmission.

10.3.5 Incretin Analogs Enhancing Memory Formation.