Document Detail

Structure-activity relationships of beta-MSH derived melanocortin-4 receptor peptide agonists.
MedLine Citation:
PMID:  17584126     Owner:  NLM     Status:  MEDLINE    
The recent emergence of obesity as a major health threat in the industrialized world has intensified the search for novel and effective pharmacologic treatment. The proopiomelanocortin (POMC)-melanocortin 4 receptor (MC4R) axis has been shown to regulate food intake and energy homeostasis and is considered among the most promising antiobesity targets. Our initial efforts in this area have focused on affinity and selectivity directed optimization of the native beta-MSH(5-22) sequence and resulted in the discovery of a potent MC4R agonist: Ac-Tyr-Arg-[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH(2) (10). Subcutaneous administration of this peptide produced an excellent in vivo efficacy in reducing food intake and increasing fat metabolism. Additionally, suppression of food intake was observed in wild type but not in MC4R deficient mice, suggesting that the effects observed in the wild type mice were mediated through MC4R signaling. Subsequent optimization efforts led to the identification of a novel series of disulfide constrained hexapeptides as exemplified by Ac-[hCys-His-D-Phe-Arg-Trp-Cys]-NH(2) (100). These cyclic hexapeptides showed a further improved potency in binding MC4R and an enhanced selectivity over MC1R. At a dose of 0.07 mg/kg analog 102 reduced food intake by 38% and increased fat utilization by 58% in rats. These cyclic peptides provide novel and enhanced reagents for the elucidation of melanocortin receptors biology and may find applications in the treatment of obesity and related metabolic disorders.
Liang Zeng Yan; Hansen M Hsiung; Mark L Heiman; Robert A Gadski; Paul J Emmerson; JeAnne Hertel; David Flora; Patrick Edwards; Dave Smiley; Lianshan Zhang; Saba Husain; Steven D Kahl; Richard D DiMarchi; John P Mayer
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Current topics in medicinal chemistry     Volume:  7     ISSN:  1873-4294     ISO Abbreviation:  Curr Top Med Chem     Publication Date:  2007  
Date Detail:
Created Date:  2007-06-22     Completed Date:  2007-09-24     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101119673     Medline TA:  Curr Top Med Chem     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1052-67     Citation Subset:  IM    
Lilly Research Laboratories, A Division of Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
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MeSH Terms
Amino Acids / chemistry
Computer Simulation
Disulfides / chemistry
Receptor, Melanocortin, Type 4 / agonists*,  metabolism
Structure-Activity Relationship
beta-MSH / chemical synthesis,  chemistry*,  pharmacology*
Reg. No./Substance:
0/Amino Acids; 0/Disulfides; 0/Receptor, Melanocortin, Type 4; 0/beta-MSH

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