Melanocortins (eBook)

ANNA CATA NIA, MD, PhD is a director of Center for Preclinical Investigation at Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy. She received her degree in Medicine and Surgery at the University of Milan and postdoctoral degree in Endocrinology and Metabolism at the University of Genoa, Italy. For over a decade she has been visiting scientist at The University of Texas Southwestern Medical Center at Dallas, Texas. During the past 20 years, her research activity has been focused on molecular biology and preclinical testing of melanocortins.

Title Page 3
Copyright Page 4
DEDICATION 5
FOREWORD 6
PREFACE 8
ABOUT THE EDITOR... 10
PARTICIPANTS 11
Table of Contents 15
Chapter 1 Structure-Activity Relationships (SAR)of Melanocortin and Agouti-Related(AGRP) Peptides 19
Introduction 19
Structure and Chemistry of Melanocortin Peptides 20
Structure-Activity Relationships (SAR) 20
Linear Melanocortin Peptides 21
a-MSH 21
Tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 22
N-Terminus Modifications 24
ß-MSH 26
.MSH 26
ACTH 27
NDP-MSH 27
SAR of Cyclic Melanocortin Peptides 27
Agouti-Related Protein (AGRP) 29
AGRP Structure 29
AGRP SAR 29
Development of Chimeric Peptide Analogues 31
Conclusion 32
References 32
Chapter 2 Melanocortin Signalling Mechanisms 37
Introduction 37
Melanocortin Receptors 38
Melanocortins and Pigmentation 39
Melanocortin Anti-Inflammatory and Immunomodulatory Roles 40
Intracellular Signalling of Melanocortin Peptides 40
Melanocortin Receptor Antagonists and Agonists 43
Conclusion 44
References 44
Chapter 3 Distribution and Function of Melanocortin Receptors within the Brain 47
Introduction 47
MC1R Is Expressed in the Periaqueductal Gray and the MC1R Regulates Pain and Analgesia 48
MC2R Is Expressed in Teleost Fish Brain and Fetal Mouse Brain, but Not in Adult Mammalian Brain 49
MC3R Is Specifically Expressed in Hypothalamus and the LimbicSystem Where Its Functions Are Not Clearly Understood 49
Adult Brain 49
Fetal and Postnatal Brain 50
Functions for MC3R in Brain 51
MC4R Is Expressed in Distinct Nuclei in Every Region of the BrainReflecting It’s Many Diverse Functions in the Brain 52
Adult Brain 52
Fetal and Postnatal Brain 53
Functions for MC4R in the Brain 53
MC5R Expression and Function in the Brain Is Unclear 56
Melanocortin Receptor Accessory Proteins (MRAPs) 57
Conclusion 57
References 60
Chapter 4 Drugs, Exercise, and the Melanocortin-4 Receptor— Different Means, Same Ends: Treating Obesity 67
Introduction 67
Melanocortins 68
Exercise 72
Conclusion 75
References 75
Chapter 5 Melanocortins in Brain Inflammation: The Role of Melanocortin Receptor Subtypes 79
Introduction 79
Distribution of MC Expressing Neurons and MC Receptors in the Brain 79
MCR Subtypes and Brain Inflammation 81
Main Intracellular Signalling Pathways of MC Receptors 82
Potential Therapeutic Applications of MC Receptor Subtype Selective Compounds 84
Conclusion 86
References 86
Chapter 6 Melanocortins and the Cholinergic Anti-Inflammatory Pathway 89
Introduction 89
The Inflammatory Reflex 90
Antishock Effects of Melanocortins 91
Melanocortins Reverse Circulatory Shock through Activationof the Cholinergic Anti-Inflammatory Pathway 92
Protective Effect of Melanocortins in Myocardial Ischemia/Reperfusion 94
Melanocortins Prevent Myocardial Ischemia/Reperfusion-InducedDamage through Activation of the Cholinergic Anti-InflammatoryPathway 95
Neuroprotection by Melanocortins in Ischemic Stroke 96
Melanocortins Produce Neuroprotection Against Ischemic Strokeby Activating the Cholinergic Anti-Inflammatory Pathway 97
Conclusion 99
References 100
Chapter 7 Melanocortin Control of Cell Trafficking in Vascular Inflammation 106
Introduction 106
Inflammation: Cell Trafficking and Microcirculation 107
Melancortins in Experimental Inflammation 108
Effects of Melanocortins on Inflammatory Cells In Vitro 115
Monocytes and Macrophages 115
Mast Cells 116
Neutrophils 117
Endothelial Cells 117
Other Cells 117
Lessons from Melanocortin Knockout Mice 118
Drug Discovery Melanocortin Peptide Pharmacology 119
Conclusion 120
References 121
Chapter 8 Terminal Signal: Anti-Inflammatory Effects of a-Melanocyte-Stimulating Hormone Related Peptides Beyond the Pharmacophore 125
Introduction 125
a-MSH Related Peptides and Melanocortin Receptors—Mediation of Anti-Inflammatory Effects? 126
Anti-Inflammatory Effects of a-MSH Related Tripeptides In Vitroand Vivo 128
Therapeutic Potential of a-MSH-Related Tripeptides in HumanImmune-Mediated Inflammatory Diseases 130
Conclusion 132
References 132
Chapter 9 Protective Effects of Melanocortins in Systemic Host Reactions 135
Introduction 135
Fever 136
Endotoxemia and Septic Shock 138
Acute Respiratory Distress Syndrome (ARDS) 139
Ischemia and Reperfusion Injury 139
Organ Transplantation 140
Conclusion 141
References 141
Chapter 10 Development of a-Melanocortin Analogs for Melanoma Prevention and Targeting 144
Introduction 144
a-Melanocortin Analogs as Tanning Agents 145
a-Melanocortin Analogs Reduce UV-Induced DNA Damage 146
a-Melanocortin Analogs for Melanoma Targeting 147
Conclusion 148
References 149
Chapter 11 MSH Radiopeptides for Targeting Melanoma Metastases 151
Introduction 151
Radionuclides and Chelators for MSH Peptides 152
MSH with High Potency for Melanoma Targeting 152
Nonspecific Targeting 156
Relevant Lead Compounds 156
Conclusion 158
References 159
Chapter 12 Applications of the Role of a-MSH in Ocular Immune Privilege 161
Ocular Immune Privilege 161
a-MSH in the Eye 162
Melanocortin Receptors and the Eye 163
Application of a-MSH in Ocular Therapy 163
Conclusion 165
References 165
INDEX 168