The role of melanocortins in body weight regulation: opportunities for the treatment of obesity

Five G-protein-coupled melanocortin receptors (MC(1)-MC(5)) are expressed in mammalian tissues. The melanocortin receptors support diverse physiological functions, including the regulation of hair color, adrenal function, energy homeostasis, feed efficiency, sebaceous gland lipid production and immune and sexual function. The melanocortins (adrenocorticotropic hormone (ACTH), alpha-melanocyte-stimulating hormone (alpha-MSH), beta-MSH and gamma-MSH) are agonist peptide ligands for the melanocortin receptors and these peptides are processed from the pre-prohormone proopiomelanocortin (POMC). Peptide antagonists for the melanocortin MC(1), MC(3) and MC(4) receptors include agouti-related protein (AgRP) and agouti. Diverse lines of evidence, including genetic and pharmacological data obtained in rodents and humans, support a role for the melanocortin MC(3) and MC(4) receptors in the regulation of energy homeostasis. Recent advances in the development of potent and selective peptide and non-peptide melanocortin receptor ligands are anticipated to help unravel the roles for the melanocortin receptors in humans and to accelerate the clinical use of small molecule melanocortin mimetics.     

The role of melanocortins in body weight regulation: opportunities for the treatment of obesity

Five G-protein-coupled melanocortin receptors (MC₁–MC₅) are expressed in mammalian tissues. The melanocortin receptors support diverse physiological functions, including the regulation of hair color, adrenal function, energy homeostasis, feed efficiency, sebaceous gland lipid production and immune and sexual function. The melanocortins (adrenocorticotropic hormone (ACTH), -melanocyte-stimulating hormone (-MSH), β-MSH and γ-MSH) are agonist peptide ligands for the melanocortin receptors and these peptides are processed from the pre-prohormone proopiomelanocortin (POMC). Peptide antagonists for the melanocortin MC₁, MC₃ and MC₄ receptors include agouti-related protein (AgRP) and agouti. Diverse lines of evidence, including genetic and pharmacological data obtained in rodents and humans, support a role for the melanocortin MC₃ and MC₄ receptors in the regulation of energy homeostasis. Recent advances in the development of potent and selective peptide and non-peptide melanocortin receptor ligands are anticipated to help unravel the roles for the melanocortin receptors in humans and to accelerate the clinical use of small molecule melanocortin mimetics.     

Recent advances in the development of melanocortin-4 receptor agonists

The melanocortin receptors are an area of intense current research, both in academia and in the pharmaceutical industry. The large body of evidence to support a critical role for the melanocortin-4 receptor (MC₄R) in energy homeostasis (as well as indications of involvement in other interesting physiological processes) has prompted research efforts to investigate its pharmacology. This review will focus on recent advances toward the identification of potential therapeutic agents working via activation of MC₄R, supplementing the more general review on ‘Ligands to the melanocortins’ published in this journal in 2001 [1]. Several patent applications have been filed in the last year on compounds with MC₄R agonist activity for a variety of indications, most notably the treatment of feeding and body weight disorders and sexual dysfunction.     

Role of central serotonin and melanocortin systems in the control of energy balance

Body weight homeostasis is critically dependent upon the convergence and integration of multiple central and peripheral signalling systems that collectively function to detect and elicit physiological and behavioural responses to nutritional state. To date, only a minority of these signals have been pharmacologically targeted for the treatment of human obesity. One signal that has been effectively manipulated to reduce body weight is the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT); however, the relevant downstream signalling pathways are incompletely understood. Recently, the melanocortin system, a nexus for multiple modulators of energy balance, has emerged as one key mediator of serotonin's effects on appetite. Here we review the serotonin and melanocortin systems with reference to their roles in energy balance and discuss the evidence that the two systems are functionally linked.     

Ligands of the melanocortin receptors, 2002 – 2003 update

α-Melanocyte-stimulating hormone (α-MSH), an endogenous ligand for the melanocortin receptors, has been long recognised as a mediator of numerous physiological processes including, among others, energy homeostasis, immunity, inflammation, sexual function, pigmentation and neurite outgrowth. Compounds mimicking or suppressing actions of α-MSH could therefore be useful in the treatment of many clinically important conditions. Since the cloning of the five melanocortin receptors, medicinal chemistry efforts have centred on the development of melanocortin-4 receptor-specific agonists for the treatment of obesity and erectile dysfunction. Yet, the growing research interest in the other α-MSH functions, reflected in part by the constantly increasing repertoire of ligands specific for the other melanocortin receptors, suggests that some medicinal chemistry efforts might soon be directed towards identification of compounds suitable for treating other diseases. In previous reviews in this journal, the pharmacology of the melanocortin receptors and melanocortin receptor ligands has been discussed in detail. This article will only report the newest ligands, those disclosed in patents published at the end of 2002 and in 2003.     

Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction

The melanocortin system has multifaceted roles in the control of body weight homeostasis, sexual behaviour and autonomic functions, and so targeting this pathway has immense promise for drug discovery across multiple therapeutic areas. In this Review, we first outline the physiological roles of the melanocortin system, then discuss the potential of targeting melanocortin receptors by using MC3 and MC4 agonists for treating weight disorders and sexual dysfunction, and MC4 antagonists to treat anorectic and cachectic conditions. Given the complexity of the melanocortin system, we also highlight the challenges and opportunities for future drug discovery in this area.     

Progress in the development of melanocortin receptor selective ligands

The melanocortin pathway consists of endogenous agonists, antagonists, G-protein coupled receptors (GPCRs), and auxiliary proteins. This pathway has been identified to participate physiologically in numerous biological pathways including energy homeostasis, pigmentation, sexual function, inflammation, cardiovascular function, adrenal function, sebaceous gland lipid production, just to list a few. During this past decade, a clear link between the melanocortin-4 receptor (MC4R) and obesity, in both mice and humans via the regulation of food intake and energy homeostasis, has made this pathway the target of many academic and industrial research endeavors in attempts to develop potent and selective MC4R small molecules as anti-obesity therapeutic agents. Herein, we attempt to summarize the known proteins that constitute the melanocortin system and discuss advances in peptide and non-peptide drug discovery.     

Synthesis and activity of the melanocortin Xaa‐d‐Phe‐Arg‐Trp‐NH2 tetrapeptides with amide bond modifications

Abstract: The melanocortin receptor (MCR) pathway has been identified as participating in several physiologically important pathways including pigmentation, energy homeostasis, inflammation, obesity, hypertension, and sexual function. All the endogenous MCR agonists contain a core His‐Phe‐Arg‐Trp sequence identified as important for receptor molecular recognition and stimulation. Several structure–activity studies using the Ac‐His‐d ‐Phe‐Arg‐Trp‐NH₂ tetrapeptide template have been performed in the context of modifying N‐terminal ‘capping’ groups and amino acid constituents. Herein, we report the synthesis and pharmacologic characterization of modified Xaa‐d ‐Phe‐Arg‐Trp‐NH₂ (Xaa = His or Phe) melanocortin tetrapeptides (N‐site selective methylation, permethylation, or amide bond reduction) at the mouse MC1, MC3, MC4 and MC5 receptors. The modified peptides generated in this study resulted in equipotent or reduced MCR potency when compared with control ligands. The reduced amide bond analog of the Phe‐d ‐Phe‐Arg‐Trp‐NH₂ peptide converted its agonist activity into an antagonistic at the central mMC3 and mMC4 receptors involved in the regulation of energy homeostasis, while retaining full agonist activity at the peripheral MC1 and MC5 receptors.     

Physiological roles of the melanocortin MC3 receptor

The melanocortin MC₃ receptor remains the most enigmatic of the melanocortin receptors with regard to its physiological functions. The receptor is expressed both in the CNS and in multiple tissues in the periphery. It appears to be an inhibitory autoreceptor on proopiomelanocortin neurons, yet global deletion of the receptor causes an obesity syndrome. Knockout of the receptor increases adipose mass without a readily measurable increase in food intake or decrease in energy expenditure. And finally, no melanocortin MC₃ receptor null humans have been identified and associations between variant alleles of the melanocortin MC₃ receptor and diseases remain controversial, so the physiological role of the receptor in humans remains to be determined.     

Investigational therapies in the treatment of obesity

Obesity is a major public health concern and environmental factors are involved in its development. The hypothalamus is a primary site for the integration of signals for the regulation of energy homeostasis. Dysregulation of these pathways can lead to weight loss or gain. Some drugs in development can have favourable effects on body weight, acting on some of these pathways and leading to responses resulting in weight loss. Strategies for the management of weight reduction include exercise, diet, behavioural therapy, drug therapy and surgery. Investigational antiobesity medications can modulate energy homeostasis by stimulating catabolic or inhibiting anabolic pathways. Investigational drugs stimulating catabolic pathways consist of leptin, agonists of melanocortin receptor-4, 5-HT and dopamine; bupropion, growth hormone fragments, cholecystokinin subtype 1 receptor agonist, peptide YY_3-36, oxyntomodulin, ciliary neurotrophic factor analogue, β3-adrenergic receptor agonists, adiponectin derivatives and glucagon-like peptide-1. On the other hand, investigational drugs inhibiting anabolic pathways consist of the ghrelin receptor, neuropeptide Y receptor and melanin-concentrating hormone-1 antagonists; somatostatin analogues, peroxisome proliferator-activated receptor-γ and -β/δ antagonists, gastric emptying retardation agents, pancreatic lipase inhibitors, topiramate and cannabinoid-1 receptor antagonists. These differing approaches are reviewed and commented on in this article.     

Structure-activity relationships of melanocortin agonists containing the benzimidazole scaffold

The melanocortin system has been implicated in regulating various physiological processes including pigmentation, energy homeostasis, obesity, steroidogenesis cardiovascular, and exocrine gland function. The five melanocortin receptors that belong to the super family of G protein-coupled receptors are stimulated by naturally occurring agonists. The aim of this research was focused on the design, synthesis, and pharmacological characterization of melanocortin ligands that contain the 1,2,5-trisubstituted benzimidazole scaffold. A series of benzimidazole analogues, with three points of diversity at positions 1, 2, and 5, were designed, synthesized, pharmacologically assayed at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R and resulted in ligands possessing a range of agonist activity from nm to no stimulation at up to 100 microM concentrations. This study demonstrates that the benzimidazole structure template can be appended with key melanocortin agonist amino acids for the design melanocortin receptor agonist ligands.     

GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism

The hypothalamic arcuate nucleus contains two anatomically and functionally distinct populations of neurons—the agouti-related peptide (AgRP)- and pro-opiomelanocortin (POMC)-expressing neurons that integrate various nutritional, hormonal, and neuronal signals to regulate food intake and energy expenditure, and thereby help achieve energy homeostasis. AgRP neurons, also co-release neuropeptide Y (NPY) and γ-aminobutyric acid (GABA) to promote feeding and inhibit metabolism through at least three possible mechanisms: (1) suppression of the melanocortin signaling system through competitive binding of AgRP with the melanocortin 4 receptors; (2) NPY-mediated inhibition of post-synaptic neurons that reside in hypothalamic nuclei; (3) GABAergic inhibition of POMC neurons in their post-synaptic targets including the parabrachial nucleus (PBN), a brainstem structure that relays gustatory and visceral sensory information. Acute ablation of AgRP neurons in adult mice by the action of diphtheria toxin (DT) results in precipitous reduction of food intake, and eventually leads to starvation within 6 days of DT treatment. Chronic delivery of bretazenil, a GABA_A receptor partial agonist, into the PBN is sufficient to restore feeding and body weight when AgRP neurons are ablated, whereas chronic blockade of melanocortin 4 receptor signaling is inadequate. This review summarizes the physiological roles of a neural circuitry regulated by AgRP neurons in control of feeding behavior with particular emphasis of the GABA output to the parabrachial nucleus. We also describe a compensatory mechanism that is gradually engaged after ablation of AgRP neurons that allows mice to continue eating without them.     

Structure-activity relationships of the unique and potent agouti-related protein (AGRP)-melanocortin chimeric Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH2 peptide template

The melanocortin receptor system consists of endogenous agonists, antagonists, G-protein coupled receptors, and auxiliary proteins that are involved in the regulation of complex physiological functions such as energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. Herein, we report the structure-activity relationship (SAR) of a new chimeric hAGRP-melanocortin agonist peptide template Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) that was characterized using amino acids previously reported in other melanocortin agonist templates. Twenty peptides were examined in this study, and six peptides were selected for (1)H NMR and computer-assisted molecular modeling structural analysis. The most notable results include the identification that modification of the chimeric template at the His position with Pro and Phe resulted in ligands that were nM mouse melanocortin-3 receptor (mMC3R) antagonists and nM mouse melanocortin-4 receptor (mMC4R) agonists. The peptides Tyr-c[beta-Asp-His-DPhe-Ala-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) and Tyr-c[beta-Asp-His-DNal(1')-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) resulted in 730- and 560-fold, respectively, mMC4R versus mMC3R selective agonists that also possessed nM agonist potency at the mMC1R and mMC5R. Structural studies identified a reverse turn occurring in the His-DPhe-Arg-Trp domain, with subtle differences observed that may account for the differences in melanocortin receptor pharmacology. Specifically, a gamma-turn secondary structure involving the DPhe(4) in the central position of the Tyr-c[beta-Asp-Phe-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) peptide may differentiate the mixed mMC3R antagonist and mMC4R agonist pharmacology.     

The 1,4-benzodiazepine-2,5-dione small molecule template results in melanocortin receptor agonists with nanomolar potencies

The melanocortin system consists of five seven-transmembrane spanning G-protein coupled receptors (MC1-5) that are stimulated by endogenous agonists and antagonized by the only two known endogenous antagonists of GPCRs, agouti and agouti-related protein (AGRP). These receptors have been associated with many physiological functions, including the involvement of the MC4R in feeding behavior and energy homeostasis, making this system an attractive target for the treatment of obesity. Small-molecule mimetics of endogenous ligands may result in the development of compounds with properties more suitable for use as therapeutic agents. The research presented herein involves the synthesis and analysis of 12 melanocortin receptor agonists using the 1,4-benzodiazepine-2,5-dione template and is the first report of these derivatives as melanocortin receptor agonists. Structure-activity relationship studies using this privileged structure template has resulted in molecules with molecular weights around 400 that possess nanomolar agonist potency at the melanocortin receptors examined in this study.     

A unifying hypothesis of Alzheimer's disease. I. Ageing sets the stage

In a series of five papers, evidence from neurobiology, endocrinology and immunology is integrated into a holistic, coherent hypothesis accommodating genetic, medical and environmental risk factors into a cascade of pathophysiological events that leads to the clinical manifestation of Alzheimer's disease (AD). The perturbation of the calcium‐energy‐oxidative stress triangle emerges as pathophysiological leitmotif of ageing and AD. Cellular Ca²⁺ homeostasis and energy metabolism are closely interdependent. Ca²⁺ ions regulate the activity of a variety of rate‐limiting enzymes of the tricarboxylic acid cycle and respiratory chain. Under physiological circumstances, the supply of energy according to demand is regulated by Ca²⁺ cycling across mitochondrial membranes. In certain pathological conditions, Ca²⁺ uncouples electron transfer and oxidative phosphorylation and increases the mitochondrial production of oxygen radicals which in tandem with Ca²⁺ precipitate the breakdown of mitochondrial function and structure. As most important risk factor, ageing sets the stage for the development of AD. The delicate regulation of the neuroendocrine network which physiologically modulates the Ca²⁺‐energy‐redox homeostasis, deteriorates in ageing, compromising the hormonal balance between neurotrophic/protective and neuroaggressive factors. Thus, levels and/or signal transduction pathways of neurotrophic‐factors such as neuropeptide Y, neurotrophins, DHEA/DHEAS, gonadal hormones, melatonin, insulin, insulin‐like growth factors, somatostatin, thyroid hormones, and substance P decay, paralleled by the compromise of the hypothalmic‐pituitary‐adrenal (HPA)‐axis feedback inhibition leading to a hyperresponsiveness to stress and a loss of diurnal rhythm of secretion of neuroaggressive glucocorticoids. Both add up to disrupt Ca²⁺ and energy homeostasis, put the nerve cells under metabolic and oxidative stress and lead to a compromise of neuronal excitability, signal transduction processes and neuronal plasticity. Subject to the same endocrinological dysregulation, the ageing immune system exhibits a primitive response pattern with impairment of specific cellular and activation of unspecific humoral and microglial immune responses. Thus, the ageing‐related concerted perturbation of the homeostatic control in the neuroendocrino‐immunological network creates phenomena which in many aspects are qualitatively similar to changes in AD and lay the foundations for the development of the disease. Copyright © 1999 John Wiley & Sons, Ltd.     

Constitutive receptor activity series: endogenous inverse agonists and constitutive receptor activity in the melanocortin system

The recent discovery of melanocortin receptor mutations that selectively decrease constitutive receptor activity in obese individuals supports the physiological relevance of constitutive melanocortin receptor activity and its control by an endogenous inverse agonist. Furthermore, studies using mice that lack endogenous melanocortin receptor agonists show that differences in coat color are caused by different degrees of constitutive melanocortin receptor signaling regulated by an endogenous inverse agonist. Thus, the regulation of constitutive activity of melanocortin receptors is important for the normal control of pigmentation and body-weight homeostasis.     

中枢神经系统钙稳态失调在阿尔采末病发病机制中的作用

阿尔采末病与衰老和细胞内钙稳态的失调等因素有关 ;AD的发病机制中多种因素可以使神经元 [Ca2 + ]i 平衡失调 ,而 [Ca2 + ]i 的升高可引起兴奋性毒性反应、自由基损伤、Tau蛋白的积聚和过度磷酸化、Aβ的毒性增大、激活Cal pain以及诱发细胞凋亡。该文综述了最近关于钙平衡失调假说的有关进展。     

黑皮质素受体4激动剂研究进展

分布在中枢神经系统的黑皮质素受体4(melanocortin receptor4,MC4R)具有控制食欲、调节体脂平衡以及改变性行为等作用,其激动剂可用于肥胖和性功能障碍的治疗。本文综述了MC4R肽类和非肽类激动剂的研究进展。     

The role of melanocortin peptides and receptors in regulation of energy balance

Energy balance is a highly regulated, complex process which is modulated by central and peripheral systems. Dysregulation of energy homeostasis can result in metabolic disorders, such as obesity and type II diabetes. Obesity and type II diabetes are two of the most prevalent and challenging clinical conditions in society today. A growing body of evidence has implicated the melanocortin system as an important component in the maintenance of energy balance. alpha-MSH, a 13 amino acid peptide secreted as a product of the pro-opiomelanocortin (POMC) gene in the pituitary is a potent agonist of 4 of the 5 cloned melanocortin receptors (MCR). MC receptors are members of a G-protein-coupled receptor (GPCR) family, which signal through cAMP. Agouti and agouti-related protein (AGRP) are natural antagonists of melanocortin receptors and participate in regulation of skin/fur pigmentation, body weight, and adiposity. Stimulation of MC receptors has pleiotropic effects, which impact the nervous system as well as endocrine and immune functions. One of the most prominent effects of MC receptor stimulation is a dramatic suppression of food intake and body weight, which has led to the hypothesis that the MC receptor system plays a primary role in the maintenance of energy balance. This idea is supported by a large body of pharmacological, molecular and human genetic evidence. The following review summarizes the role of melanocortin receptors in the regulation of food intake and energy homeostasis and highlights the opportunities for MC receptors as drug development targets in treating eating disorders and diabetes.