Structure-Activity Relationship Studies on a Macrocyclic Agouti-Related Protein (AGRP) Scaffold Reveal Agouti Signaling Protein (ASP) Residue Substitutions Maintain Melanocortin-4 Receptor Antagonist Potency and Result in Inverse Agonist Pharmacology at the Melanocortin-5 Receptor

Mark D. Ericson, Katie T. Freeman, Sathya M. Schnell, Katlyn A. Fleming, Carrie Haskell-Luevano

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The melanocortin system consists of five reported receptors, agonists from the proopiomelanocortin gene transcript, and two antagonists, agouti-signaling protein (ASP) and agouti-related protein (AGRP). For both ASP and AGRP, the hypothesized Arg-Phe-Phe pharmacophores are on exposed β-hairpin loops. In this study, the Asn and Ala positions of a reported AGRP macrocyclic scaffold (c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro]) were explored with 14-compound and 8-compound libraries, respectively, to generate more potent, selective melanocortin receptor antagonists. Substituting diaminopropionic acid (Dap), DDap, and His at the Asn position yielded potent MC4R ligands, while replacing Ala with Ser maintained MC4R potency. Since these substitutions correlate to ASP loop residues, an additional Phe to Ala substitution was synthesized and observed to maintain MC4R potency. Seventeen compounds also possessed inverse agonist activity at the MC5R, the first report of this pharmacology. These findings are useful in developing molecular probes to study negative energy balance conditions and unidentified functions of the MC5R.

Original languageEnglish (US)
Pages (from-to)8103-8114
Number of pages12
JournalJournal of medicinal chemistry
Volume60
Issue number19
DOIs
StatePublished - Oct 12 2017

Bibliographical note

Funding Information:
Figure 1C was generated using the PDB files 1Y7K29 and 1HYK50 and using PyMOL Molecular Graphics System, version 1.7.0.5, Schrödinger, LLC, with the computing resources of the University of Minnesota Supercomputing Institute. This work has been supported by NIH Grant R01DK091906 (C.H.-L.). M.D.E. is a recipient of an NIH F32 Postdoctoral Fellowship (Grant F32DK108402).

Publisher Copyright:
© 2017 American Chemical Society.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

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