Peptoid mimics of agouti related protein

• Published in: Bioorganic & medicinal chemistry letters 2003-04, Vol.13 (8), p.1409-1413
• Main Authors: Thompson, Darren A., Chai, Biao-Xin, Rood, Hilary L.E., Siani, Michael A., Douglas, Nicholai R., Gantz, Ira, Millhauser, Glenn L.
• Format: Article
• Language: English
• Subjects: Agouti-Related Protein; alpha-MSH - antagonists & inhibitors; alpha-MSH - pharmacology; Biological and medical sciences; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Cyclic AMP - metabolism; Dose-Response Relationship, Drug; Drug Design; Hormones. Endocrine system; Humans; Inhibitory Concentration 50; Intercellular Signaling Peptides and Proteins; Medical sciences; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Peptoids - chemistry; Peptoids - pharmacology; Pharmacology. Drug treatments; Proteins - chemistry; Proteins - physiology; Radioligand Assay; Receptors, Melanocortin - agonists; Receptors, Melanocortin - antagonists & inhibitors; Receptors, Melanocortin - metabolism
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00164-1

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-α-MSH (IC 50=3.1 μM) and AGRP (86–132) (IC 50=1.9 μM) from the human melanocortin-4 receptor and functioned as an antagonist of α-MSH stimulated cAMP generation, thus providing an important lead in the development of AGRP mimetics. A peptoid antagonist of the human Melanocortin 4 Receptor 5 (IC 50=1.9 μM) is reported.