Discovery of a β‑Hairpin Octapeptide, c[Pro-Arg-Phe-Phe-Dap-Ala-Phe-DPro], Mimetic of Agouti-Related Protein(87–132) [AGRP(87–132)] with Equipotent Mouse Melanocortin‑4 Receptor (mMC4R) Antagonist Pharmacology

Agouti-related protein (AGRP) is a potent orexigenic peptide that antagonizes the melanocortin-3 and -4 receptors (MC3R and MC4R). While the C-terminal domain of AGRP, AGRP(87–132), is equipotent to the full-length peptide, further truncation decreases potency at the MC3R and MC4R. Herein, we report...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2015-06, Vol.58 (11), p.4638-4647
Main Authors: Ericson, Mark D, Wilczynski, Andrzej, Sorensen, Nicholas B, Xiang, Zhimin, Haskell-Luevano, Carrie
Format: Article
Language:English
Subjects:
Agouti-Related Protein - chemistry
Animals
Biomimetics
Cyclic AMP - metabolism
Drug Discovery
HEK293 Cells
Humans
Ligands
Mice
Models, Molecular
Molecular Structure
Peptide Fragments - chemistry
Peptide Fragments - pharmacology
Receptor, Melanocortin, Type 3 - antagonists & inhibitors
Receptor, Melanocortin, Type 4 - antagonists & inhibitors
Structure-Activity Relationship
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Summary:Agouti-related protein (AGRP) is a potent orexigenic peptide that antagonizes the melanocortin-3 and -4 receptors (MC3R and MC4R). While the C-terminal domain of AGRP, AGRP(87–132), is equipotent to the full-length peptide, further truncation decreases potency at the MC3R and MC4R. Herein, we report AGRP-derived peptides designed to mimic the active β-hairpin secondary structure that contains the hypothesized Arg-Phe-Phe pharmacophore. The most potent scaffold, c­[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro], comprised the hexa-peptide β-hairpin loop from AGRP cyclized through a DPro–Pro motif. A 20 compound library was synthesized from this scaffold for further structure–activity relationship studies. The most potent peptide from this library was an asparagine to diaminopropionic acid substitution that possessed sub-nanomolar antagonist activity at the mMC4R and was greater than 160-fold selective for the mMC4R versus the mMC3R. The reported ligands may serve as probes to characterize the melanocortin receptors in vivo and leads in the development of novel therapeutics.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b00184