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

doi:10.1021/acs.jmedchem.8b00684

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

Medicinal Chemistry

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10 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 language	English (US)
Pages (from-to)	7729-7740
Number of pages	12
Journal	Journal of medicinal chemistry
Volume	61
Issue number	17
DOIs	https://doi.org/10.1021/acs.jmedchem.8b00684
State	Published - 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.

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Fleming, K. A., Freeman, K. T., Ericson, M. D., & Haskell-Luevano, C. (2018). 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. Journal of medicinal chemistry, 61(17), 7729-7740. https://doi.org/10.1021/acs.jmedchem.8b00684

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. / Fleming, Katlyn A.; Freeman, Katie T.; Ericson, Mark D. et al.
In: Journal of medicinal chemistry, Vol. 61, No. 17, 13.09.2018, p. 7729-7740.

Research output: Contribution to journal › Article › peer-review

Fleming, KA, Freeman, KT, Ericson, MD & Haskell-Luevano, C 2018, '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', Journal of medicinal chemistry, vol. 61, no. 17, pp. 7729-7740. https://doi.org/10.1021/acs.jmedchem.8b00684

Fleming KA, Freeman KT, Ericson MD, Haskell-Luevano C. 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. Journal of medicinal chemistry. 2018 Sep 13;61(17):7729-7740. doi: 10.1021/acs.jmedchem.8b00684

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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.",

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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

Abstract

Bibliographical note

UN SDGs

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