Abstract
The melanocortin family of receptors (MC 1 - 5R) and their endogenous peptide ligands (α, β, γ - MSH and ACTH) have been implicated in the control of a wide variety of behavioral and physiological functions including the homeostatic control of food intake and body weight. In rodent models, melanocortin agonists including the nonselective peptide MTII have been shown to decrease food intake and body weight while antagonists such as SHU9119 and AGRP have been shown to stimulate food intake and increase body weight. Deletion of either the MC3R or MC4R in mice was found to be associated with obesity although hyperphagia was only observed in the MC4R deficient mice. Similarly in humans, inactivating mutations of the MC4R have been found in as many as six percent of obese individuals. The suggestion from these findings that activation of MC4Rs would have an anorectic effect in humans has resulted in efforts to produce selective agonists for the treatment of obesity. Over the past decade, efforts to develop MC4R selective small molecule and peptide agonists have been met with fractional success. Many small molecule agonists have been identified; however, few have been shown to have activity in vivo. While their use as therapeutics may have limitations, selective and potent peptide agonists have been shown by several investigators to decrease food intake and body weight in rodent models. The subject of the current review is to examine the progress made to date on producing both small molecule and peptide MC4R agonists as potential therapeutics for obesity.
Keywords: shu9119, melanocortin-3 receptor, active melanocortin peptides corticotrophin, mc4r deficient mice, aplha-msh
Current Topics in Medicinal Chemistry
Title: Melanocortin - 4 Receptor Agonists for the Treatment of Obesity
Volume: 7 Issue: 11
Author(s): Matthew J. Fisher, Liang Zeng Yan, John P. Mayer and Paul J. Emmerson
Affiliation:
Keywords: shu9119, melanocortin-3 receptor, active melanocortin peptides corticotrophin, mc4r deficient mice, aplha-msh
Abstract: The melanocortin family of receptors (MC 1 - 5R) and their endogenous peptide ligands (α, β, γ - MSH and ACTH) have been implicated in the control of a wide variety of behavioral and physiological functions including the homeostatic control of food intake and body weight. In rodent models, melanocortin agonists including the nonselective peptide MTII have been shown to decrease food intake and body weight while antagonists such as SHU9119 and AGRP have been shown to stimulate food intake and increase body weight. Deletion of either the MC3R or MC4R in mice was found to be associated with obesity although hyperphagia was only observed in the MC4R deficient mice. Similarly in humans, inactivating mutations of the MC4R have been found in as many as six percent of obese individuals. The suggestion from these findings that activation of MC4Rs would have an anorectic effect in humans has resulted in efforts to produce selective agonists for the treatment of obesity. Over the past decade, efforts to develop MC4R selective small molecule and peptide agonists have been met with fractional success. Many small molecule agonists have been identified; however, few have been shown to have activity in vivo. While their use as therapeutics may have limitations, selective and potent peptide agonists have been shown by several investigators to decrease food intake and body weight in rodent models. The subject of the current review is to examine the progress made to date on producing both small molecule and peptide MC4R agonists as potential therapeutics for obesity.
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Matthew J. Fisher , Liang Zeng Yan , John P. Mayer and Paul J. Emmerson , Melanocortin - 4 Receptor Agonists for the Treatment of Obesity, Current Topics in Medicinal Chemistry 2007; 7 (11) . https://dx.doi.org/10.2174/156802607780906636
DOI https://dx.doi.org/10.2174/156802607780906636 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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