Abstract
The Agouti Related Protein (AGRP) is an endogenous antagonist of melanocortin-3 and -4 receptors, each of which plays a key role in body weight homeostasis. We designed a peptoid trimer based on AGRP 111-113 in which a single chiral atom is used to partially restrain the backbone structure. Peptoid 5 displaced both radiolabeled Nle4-alpha-MSH (IC(50)=3.1 microM) and AGRP (86-132) (IC(50)=1.9 microM) from the human melanocortin-4 receptor and functioned as an antagonist of alpha-MSH stimulated cAMP generation, thus providing an important lead in the development of AGRP mimetics.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Agouti-Related Protein
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Biomimetic Materials / chemistry
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Biomimetic Materials / pharmacology
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Cyclic AMP / metabolism
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Dose-Response Relationship, Drug
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Drug Design
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Humans
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Inhibitory Concentration 50
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Intercellular Signaling Peptides and Proteins
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Peptide Fragments / chemistry*
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Peptide Fragments / pharmacology
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Peptoids / chemistry*
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Peptoids / pharmacology
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Proteins / chemistry*
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Proteins / physiology
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Radioligand Assay
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Receptors, Melanocortin / agonists
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Receptors, Melanocortin / antagonists & inhibitors
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Receptors, Melanocortin / metabolism
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alpha-MSH / antagonists & inhibitors
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alpha-MSH / pharmacology
Substances
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AGRP protein, human
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Agouti-Related Protein
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Intercellular Signaling Peptides and Proteins
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Peptide Fragments
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Peptoids
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Proteins
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Receptors, Melanocortin
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agouti-related protein (86-132), human
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alpha-MSH
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Cyclic AMP