Synergistic Multiresidue Substitutions of a Macrocyclic c[Pro-Arg-Phe-Phe-Asn-Ala-Phe- d Pro] Agouti-Related Protein (AGRP) Scaffold Yield Potent and >600-Fold MC4R versus MC3R Selective Melanocortin Receptor Antagonists

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

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Antagonist ligands of the melanocortin-3 and -4 receptors (MC3R, MC4R), including agouti-related protein (AGRP), are postulated to be targets for the treatment of diseases of negative energy balance. Previous studies reported the macrocyclic MC3R/MC4R antagonist c[Pro1-Arg2-Phe3-Phe4-Asn5-Ala6-Phe7-dPro8], which is 250-fold less potent at the mouse (m) mMC3R and 3-fold less potent at the mMC4R than AGRP. Previous studies explored the structure-activity relationships around individual positions in this template. Herein, a multiresidue substitution strategy is utilized, combining the lead sequence with hPhe4, Dap5, Arg5, Ser6, and Nle7 substitutions previously reported. Two compounds from this study (16, 20) contain an hPhe4/Ser6/Nle7 substitution pattern, are 3-6-fold more potent than AGRP at the mMC4R and are 600-800-fold selective for the mMC4R over the mMC3R. Another lead compound (21), possessing the hPhe4/Arg5 substitutions, is only 5-fold less potent than AGRP at the mMC3R and is equipotent to AGRP at the mMC4R.

Original languageEnglish (US)
Pages (from-to)7729-7740
Number of pages12
JournalJournal of medicinal chemistry
Volume61
Issue number17
DOIs
StatePublished - Sep 13 2018

Bibliographical note

Funding Information:
This work has been supported in part by NIH Grant R01DK091906. The Haskell-Luevano laboratory is a recipient of a 2017 Wallin Neuroscience Discovery Fund Award through the University of Minnesota. M.D.E. is a recipient of an NIH F32 Postdoctoral Fellowship (F32DK108402). K.A.F. is a recipient of a 2018 Bighley Fellowship and a 2018 Rowell Fellowship.

Publisher Copyright:
© 2018 American Chemical Society.

Fingerprint

Dive into the research topics of 'Synergistic Multiresidue Substitutions of a Macrocyclic c[Pro-Arg-Phe-Phe-Asn-Ala-Phe- d Pro] Agouti-Related Protein (AGRP) Scaffold Yield Potent and >600-Fold MC4R versus MC3R Selective Melanocortin Receptor Antagonists'. Together they form a unique fingerprint.

Cite this