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Structure-activity relationships of beta-MSH derived melanocortin-4 receptor peptide agonists.
Yan, Liang Zeng; Hsiung, Hansen M; Heiman, Mark L; Gadski, Robert A; Emmerson, Paul J; Hertel, JeAnne; Flora, David; Edwards, Patrick; Smiley, Dave; Zhang, Lianshan; Husain, Saba; Kahl, Steven D; DiMarchi, Richard D; Mayer, John P.
Afiliação
  • Yan LZ; Lilly Research Laboratories, A Division of Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. yan_liang_zeng@lilly.com
Curr Top Med Chem ; 7(11): 1052-67, 2007.
Article em En | MEDLINE | ID: mdl-17584126
ABSTRACT
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.
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Beta-MSH / Receptor Tipo 4 de Melanocortina Limite: Animals / Humans Idioma: En Ano de publicação: 2007 Tipo de documento: Article
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Beta-MSH / Receptor Tipo 4 de Melanocortina Limite: Animals / Humans Idioma: En Ano de publicação: 2007 Tipo de documento: Article