| Nota di contenuto |
Intro -- Preface -- Contents -- Part I: Basics -- Fundamentals of the Dynorphins/Kappa Opioid Receptor System: From Distribution to Signaling and Function -- 1 Historical Perspectives -- 2 Dynorphin Peptides -- 3 Cloning of the KOR -- 4 Neuroanatomy of the KOR -- 5 KOR Signaling at the Cellular Level -- 6 Agonist-Promoted KOR Phosphorylation and Regulation -- 7 X-ray Crystal Structures of the KOR -- 8 In Vivo Pharmacology of the DYNs/KOR System -- 9 Conclusion -- References -- Considerations on Using Antibodies for Studying the Dynorphins/Kappa Opioid Receptor System -- 1 Introduction -- 2 General Considerations for Validation of Specificity of Antibodies -- 2.1 Unique Issues Associated with Antibodies Against G Protein-Coupled Receptors (GPCRs) -- 2.2 Validation of Specificity of Antibodies -- 3 Antibodies for IHC of the KOR -- 3.1 Characterization of KT2 Antibody and KOR1 Antibodies for IHC -- 3.2 IHC of the KOR in the Brain -- 3.3 Generation of a Mouse Line Expressing a Fusion Protein of the KOR Conjugated with tdTomato (KOR-tdT) -- 4 KOR Antibodies for IB -- 4.1 Detection of KOR Expressed in Cells -- 4.2 Detection of the KOR in Mouse Brains -- 5 Antibodies for IB of Phosphorylated KOR -- 5.1 Detection of Phosphorylated KOR in Cells -- 5.2 Detection of Phosphorylated KOR in Mouse Brains -- 5.3 U50,488H Promoted KOR Phosphorylation at T363 and S369 in Mouse Brains in a Dose-Dependent Manner -- 6 KOR Antibodies from Commercial Sources -- 7 Antibodies against Dynorphins: Some Considerations -- 8 Conclusion -- References -- Part II: In Vitro Studies -- Structural Characterization of KOR Inactive and Active States for 3D Pharmacology and Drug Discovery -- 1 Introduction -- 2 Structure Determination of KOR -- 2.1 KOR-JDTic Structure in Inactive State -- 2.2 KOR-MP1104 Structure in Active State -- 2.3 JDTic-KOR-Nb6 Structure in Inactive State.
3 Overall Architecture of the KOR in Inactive and Active States -- 4 Structural Determinants of Long-Acting Antagonist JDTic Binding in Inactive Structure -- 5 Structural Determinants of Agonist MP1104 Binding in the Active-State Structure -- 6 Large-Scale Conformational Changes in KOR as a Part of the Activation Mechanism -- 7 Structure-Based Insights into KOR 3D Pharmacology -- 7.1 KOR Antagonists: Long-Acting and Short-Acting -- 7.2 KOR Agonists -- 7.3 Determinants of Opioid Ligand Selectivity at KOR -- 8 Applications of KOR Structure to Computer-Assisted Ligand Discovery -- 8.1 Understanding KOR Dynamics by MD Simulations -- 8.2 Discovery of New KOR Chemotypes by Structure-Based Virtual Screening -- 8.3 Rational Design for KOR Selectivity Over MOR and DOR -- 8.4 Rational Design for KOR Functional Selectivity -- 9 Conclusions and Outlook -- References -- Biosensors Monitor Ligand-Selective Effects at Kappa Opioid Receptors -- 1 Introduction: Ligand-Selective Effects at the Kappa Opioid Receptor -- 2 Nanobodies and Mini-G Proteins Act as Conformation-Specific KOR Binders -- 2.1 Active State Binding Nanobodies Nb39 and Nb33 -- 2.2 Inactive State Binding Nanobody Nb6 -- 2.3 Active State Binding Mini-G Protein Mini-Gsi -- 3 Biosensors Robustly and Rapidly Report on KOR Activation and Deactivation -- 4 Biosensors Reveal Ligand-Selective Effects at KOR -- 4.1 Ligand-Selective Recruitment of Distinct Biosensors to KOR -- 4.2 Agonist-Selective Activation of KOR at Distinct Cellular Locations -- 5 Conclusions and Outlook -- References -- Does GEC1 Enhance Expression and Forward Trafficking of the Kappa Opioid Receptor (KOR) via Its Ability to Interact with NSF D... -- 1 Introduction -- 2 Experimental Procedures -- 2.1 Pull-Down Assays Using Purified Recombinant Proteins Expressed in E. coli -- 3 Results -- 4 Discussion -- References.
Kappa Opioid Receptor Mediated Differential Regulation of Serotonin and Dopamine Transporters in Mood and Substance Use Disord... -- 1 Introduction -- 2 KOR and the Serotonergic System -- 2.1 KOR Interaction with Serotonergic System and Its Relevance to Psychiatric Disorders -- 2.2 KOR Signaling in the Regulation of Serotonin Clearance: Modulation of Serotonin Transporter Function, Trafficking, and Pho... -- 3 KOR and the Dopaminergic System -- 3.1 KOR Interaction with Dopaminergic System and Its Relevance to Cocaine Use Disorder -- 3.2 KOR Signaling in the Regulation of Dopamine Clearance: Modulation of Dopamine Transporter Function and Trafficking -- 4 Dynorphin/KOR System as a Therapeutic Target -- 5 Conclusions -- References -- Part III: Preclinical Drug Development -- Biased Ligands at the Kappa Opioid Receptor: Fine-Tuning Receptor Pharmacology -- 1 Introduction: Biased Signaling and the Kappa Opioid Receptor -- 2 Signaling Cascades Downstream of the Kappa Opioid Receptor -- 2.1 G Proteins -- 2.2 βarrestin2 Activation -- 3 Physiological Implications of Signaling Pathways Downstream of the Kappa Opioid Receptor -- 4 Biased Ligands at the Kappa Opioid Receptor -- 5 Conclusions -- References -- Preclinical Studies on Nalfurafine (TRK-820), a Clinically Used KOR Agonist -- 1 Introduction -- 2 In Vitro Pharmacological Characterization of Nalfurafine -- 2.1 Bioassays -- 2.2 Binding Affinity and Selectivity Profile of Nalfurafine at MOR, DOR, KOR and NOR -- 2.3 No Significant Binding to Targets Other Than Opioid Receptors -- 2.4 Efficacies and Potencies of Nalfurafine in Activating MOR, DOR, KOR and NOR: Inhibition of Adenylate Cyclase and Enhanceme... -- 2.5 Functional Selectivity of Nalfurafine in KOR-Mediated Activation of G Proteins and β-Arrestins -- 2.6 KOR Internalization and Down-Regulation -- 3 In Vivo Pharmacological Effects of Nalfurafine.
3.1 Antipruritic Effects -- 3.2 Anti-nociceptive Effects -- 3.3 Anti-allodynic and Anti-hyperalgesic Effects -- 3.4 Inhibition of Neurogenic Inflammation -- 3.5 Aversive Effects or Lack Thereof -- 3.6 Effects on Locomotor Activity and Motor Coordination -- 3.7 Water Diuretic Effects -- 3.8 Nalfurafine and U50,488H Induced Different Phosphoproteomic Changes in Mouse Brains -- 3.9 Effect of Nalfurafine on Pharmacological Actions of Morphine -- 3.9.1 Effects on Morphine-Induced Itch -- 3.9.2 Effect on Morphine-Induced Antinociception -- 3.9.3 Effects on Rewarding Properties of Morphine and Oxycodone -- 3.9.4 Effects on Morphine-Induced Tolerance and Dependence -- 3.9.5 Effects on Morphine-Induced Hyperlocomotion -- 4 Nalfurafine as an Abuse-Deterring Agent for Prescription Opioid Abuse -- 4.1 Translational Significance of Contingent vs. Non-contingent Administration of KOR Agonists -- 4.2 Behavioral Pharmacology of Nalfurafine/Oxycodone Combinations -- 4.2.1 Studies in Rats -- 4.2.2 Studies in Nonhuman Primates -- 5 Effects of Nalfurafine on Alcohol Drinking -- 5.1 The Dynorphins/KOR System in Alcohol-Related Behaviors -- 5.2 Development of Nalfurafine as a Potential Therapeutic Agent for Alcoholism -- 6 Effect of Nalfurafine on CPP and Discriminative Stimulus Effects of Cocaine -- 7 Other Effects -- 8 Conclusion -- References -- Kappa Opioid Receptor Ligands and Pharmacology: Diphenethylamines, a Class of Structurally Distinct, Selective Kappa Opioid Li... -- 1 Introduction -- 2 KOR Ligands and Their Pharmacology -- 2.1 Natural Ligands -- 2.2 Synthetic Ligands -- 2.3 Diphenethylamines, a New Class of Selective KOR Ligands -- 2.3.1 Agonists and Partial Agonists -- 2.3.2 Biased Agonists -- 2.3.3 Antagonists -- 2.3.4 In Vivo Pharmacology -- 3 Conclusion -- References -- Peptide Kappa Opioid Receptor Ligands and Their Potential for Drug Development.
1 Introduction -- 1.1 Actions of the Endogenous Kappa Opioid System and Resultant Potential Therapeutic Applications of Ligands for Kappa Opioid... -- 1.2 Review of Key Non-Peptidic Kappa Opioid Receptor-Selective Ligands -- 2 Peptide Ligands for Kappa Opioid Receptors -- 2.1 Dynorphin A Analogs -- 2.2 Tetrapeptide KOR Ligands -- 2.2.1 All-D-Amino Acid Peptides -- 2.2.2 Endomorphin-1 Derivative -- 2.2.3 Macrocyclic Tetrapeptides -- 3 Conclusions -- References -- Part IV: Preclinical Studies: In Vivo Pharmacology -- Dynorphin/Kappa-Opioid Receptor System Modulation of Cortical Circuitry -- 1 Introduction -- 1.1 Cortical Circuits -- 1.2 Anatomy of the Cortical DYN/KOR System -- 1.3 Function of the DYN/KOR System in the Cortex -- 1.4 Behavioral Effects of the DYN/KOR System in the Cortex -- 1.5 Implication for Human Health and Diseases -- 1.6 Unknowns and Future Directions for the Field -- 1.6.1 DYN/KOR Regulation of Dendritic Integration -- 1.6.2 Conservation Across Species -- 1.6.3 Site of Psychotomimetic Effects -- 1.6.4 Interactions with Other Stress-Related Peptides/Systems -- 1.6.5 Novel Approaches to Study the DYN/KOR System -- 2 Conclusions -- References -- Molecular Genetics of Kappa Opioids in Pain and Itch Sensations -- 1 The Kappa Opioid System in Pain -- 1.1 Peripheral Effects of Dynorphins (DRG and TG Neurons) -- 1.2 Dynorphin Neurons in the Spinal Cord -- 1.3 Functions of the Dynorphin/KOR System in the Parabrachial Nucleus -- 1.4 Role of Kappa Opioids in Pain-Induced Stress Responses in the Dorsal Raphe Nucleus, Amygdala, Rostral Ventral Medulla, and... -- 1.5 Summary and Future Direction of Kappa Signaling in Control of Pain -- 2 Kappa Opioids in Itch -- 2.1 Dynorphin Spinal Cord Interneurons Inhibit Itch -- 2.2 Neuronal Circuits for Itch -- 2.3 Summary and Future Direction for Itch Research.
3 Common Mechanisms of Action of the Kappa Opioid System.
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Delta Opioid Receptor Pharmacology and Therapeutic Applications / / edited by Emily M. Jutkiewicz
