The kappa opioid receptor / Lee-Yuan Liu-Chen, Saadet Inan, editors.

Format:

Book

Contributor:

Liu-Chen, Lee-Yuan, editor.

Inan, Saadet, editor.

Series:

Handbook of experimental pharmacology ; Volume 271.

Handbook of experimental pharmacology ; Volume 271

Language:

English

Subjects (All):

Opioids--Receptors.

Opioids.

Pharmacology.

Physical Description:

1 online resource (574 pages)

Place of Publication:

Cham, Switzerland : Springer, [2022]

Summary:

This book covers the latest knowledge in structure, signaling, and biochemical pharmacology of KOR as well as preclinical research and clinical applications (including clinical phase studies and approved for human use) of KOR compounds. It is divided up into the three parts: Molecular aspects of KOR, Preclinical research on pharmacology of KOR agonists and antagonists in animals and KOR agonists and antagonists in clinical use and in past and present clinical trials. The chapters "Biosensors monitor ligand-selective effects at kappa opioid receptors" and "The role of dynorphin and the kappa opioid receptor in schizophrenia and major depressive disorder: a translational approach" of this book are available open access under a Creative Commons Attribution 4.0 International License via link.springer.com.

Contents:

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

Part II: In Vitro Studies

Structural Characterization of KOR Inactive and Active States for 3D Pharmacology and Drug Discovery

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

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

Does GEC1 Enhance Expression and Forward Trafficking of the Kappa Opioid Receptor (KOR) via Its Ability to Interact with NSF D...

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...

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

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

Preclinical Studies on Nalfurafine (TRK-820), a Clinically Used KOR Agonist

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

Kappa Opioid Receptor Ligands and Pharmacology: Diphenethylamines, a Class of Structurally Distinct, Selective Kappa Opioid Li...

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

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

Part IV: Preclinical Studies: In Vivo Pharmacology

Dynorphin/Kappa-Opioid Receptor System Modulation of Cortical Circuitry

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

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.

Notes:

Includes bibliographical references and index.

Description based on print version record.

Other Format:

Print version: Liu-Chen, Lee-Yuan The Kappa Opioid Receptor

ISBN:

3-030-89074-0

OCLC:

1286665759