Multiresidue Tetrapeptide Substitutions Yield a 140-fold Selective Melanocortin-3 over Melanocortin-4 Receptor Agonist

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2021 Jan 25

PMID 33488972

Citations 2

Authors

Mark D Ericson

Romessa Shaikh

Courtney M Larson

Katie T Freeman

Carrie Haskell-Luevano

Affiliations

Soon will be listed here.

Abstract

The five melanocortin receptors regulate numerous physiological functions. Although many ligands have been developed for the melanocortin-4 receptor (MC4R), the melanocortin-3 receptor (MC3R) has been less-well characterized, in part due to the lack of potent, selective tool compounds. Previously an Ac-His-Arg-(pI)DPhe-Tic-NH scaffold, inverting the Phe-Arg motif of the native melanocortin signal sequence, was identified to possess mMC3R over mMC4R selective agonist activity. In this study, a library of 12 compounds derived from this scaffold was synthesized and assayed at the mouse melanocortin receptors (MCRs), utilizing substitutions previously shown to increase mMC3R agonist potency and/or selectivity. One compound (, Ac-Val-Gln-DBip-DTic-NH) was identified as greater than 140-fold selective for the mMC3R over the mMC4R, possessed 70 nM potency at the mMC3R, and partially stimulated the mMC4R at 100 μM concentrations without antagonist activity. This pharmacological profile may be useful in developing new tool and therapeutic ligands that selective signal through the MC3R.

Citing Articles

Weirath N, Haskell-Luevano C ACS Pharmacol Transl Sci. 2024; 7(9):2706-2724.

PMID: 39296259 PMC: 11406693. DOI: 10.1021/acsptsci.4c00129.

Incorporation of Indoylated Phenylalanine Yields a Sub-Micromolar Selective Melanocortin-4 Receptor Antagonist Tetrapeptide.

Ericson M, Larson C, Freeman K, Nicke L, Geyer A, Haskell-Luevano C ACS Omega. 2022; 7(31):27656-27663.

PMID: 35967074 PMC: 9366794. DOI: 10.1021/acsomega.2c03307.

References

Doering S, Freeman K, Schnell S, Haslach E, Dirain M, Debevec G . Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa-Arg-(pI)DPhe-Xaa-NH. J Med Chem. 2017; 60(10):4342-4357. PMC: 5672800. DOI: 10.1021/acs.jmedchem.7b00301. View

Chen A, Marsh D, Trumbauer M, Frazier E, Guan X, Yu H . Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet. 2000; 26(1):97-102. DOI: 10.1038/79254. View

Butler A, Kesterson R, Khong K, Cullen M, Pelleymounter M, Dekoning J . A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology. 2000; 141(9):3518-21. DOI: 10.1210/endo.141.9.7791. View

Yang Z, Tao Y . Mutations in Melanocortin-3 Receptor Gene and Human Obesity. Prog Mol Biol Transl Sci. 2016; 140:97-129. DOI: 10.1016/bs.pmbts.2016.01.002. View

Mountjoy K, Robbins L, Mortrud M, Cone R . The cloning of a family of genes that encode the melanocortin receptors. Science. 1992; 257(5074):1248-51. DOI: 10.1126/science.1325670. View

Lensing C, Freeman K, Schnell S, Adank D, Speth R, Haskell-Luevano C . An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers. J Med Chem. 2016; 59(7):3112-28. PMC: 5679017. DOI: 10.1021/acs.jmedchem.5b01894. View

Huszar D, Lynch C, Dunmore J, Fang Q, Berkemeier L, Gu W . Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997; 88(1):131-41. DOI: 10.1016/s0092-8674(00)81865-6. View

Schlasner K, Ericson M, Doering S, Freeman K, Weinrich M, Haskell-Luevano C . Structure⁻Activity Relationships of the Tetrapeptide Ac-His-Arg-(I)DPhe-Tic-NH at the Mouse Melanocortin Receptors: Modification at the (I)DPhe Position Leads to mMC3R Versus mMC4R Selective Ligands. Molecules. 2019; 24(8). PMC: 6515519. DOI: 10.3390/molecules24081463. View

Kaiser E, Colescott R, Bossinger C, Cook P . Color test for detection of free terminal amino groups in the solid-phase synthesis of peptides. Anal Biochem. 1970; 34(2):595-8. DOI: 10.1016/0003-2697(70)90146-6. View

10.

Mayorov A, Cai M, Chandler K, Petrov R, Van Scoy A, Yu Z . Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities. J Med Chem. 2006; 49(6):1946-52. PMC: 1484467. DOI: 10.1021/jm0510326. View

11.

Greenfield J, Miller J, Keogh J, Henning E, Satterwhite J, Cameron G . Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med. 2008; 360(1):44-52. DOI: 10.1056/NEJMoa0803085. View

12.

Grieco P, Balse P, Weinberg D, MacNeil T, Hruby V . D-Amino acid scan of gamma-melanocyte-stimulating hormone: importance of Trp(8) on human MC3 receptor selectivity. J Med Chem. 2001; 43(26):4998-5002. DOI: 10.1021/jm000211e. View

13.

Fleming K, Freeman K, Powers M, Santos R, Debevec G, Giulianotti M . Discovery of Polypharmacological Melanocortin-3 and -4 Receptor Probes and Identification of a 100-Fold Selective nM MC3R Agonist versus a μM MC4R Partial Agonist. J Med Chem. 2019; 62(5):2738-2749. PMC: 6463894. DOI: 10.1021/acs.jmedchem.9b00053. View

14.

Hinney A, Volckmar A, Knoll N . Melanocortin-4 receptor in energy homeostasis and obesity pathogenesis. Prog Mol Biol Transl Sci. 2013; 114:147-91. DOI: 10.1016/B978-0-12-386933-3.00005-4. View

15.

Carotenuto A, Merlino F, Cai M, Brancaccio D, Yousif A, Novellino E . Discovery of Novel Potent and Selective Agonists at the Melanocortin-3 Receptor. J Med Chem. 2015; 58(24):9773-8. PMC: 5070805. DOI: 10.1021/acs.jmedchem.5b01285. View

16.

Irani B, Xiang Z, Yarandi H, Holder J, Moore M, Bauzo R . Implication of the melanocortin-3 receptor in the regulation of food intake. Eur J Pharmacol. 2011; 660(1):80-7. PMC: 3095750. DOI: 10.1016/j.ejphar.2010.10.101. View

17.

Van der Ploeg L, Martin W, Howard A, Nargund R, Austin C, Guan X . A role for the melanocortin 4 receptor in sexual function. Proc Natl Acad Sci U S A. 2002; 99(17):11381-6. PMC: 123265. DOI: 10.1073/pnas.172378699. View

18.

Singh A, Tala S, Flores V, Freeman K, Haskell-Luevano C . Synthesis and Pharmacology of α/β(3)-Peptides Based on the Melanocortin Agonist Ac-His-dPhe-Arg-Trp-NH2 Sequence. ACS Med Chem Lett. 2015; 6(5):568-72. PMC: 4434477. DOI: 10.1021/acsmedchemlett.5b00053. View

19.

SCHILD H . pA, a new scale for the measurement of drug antagonism. Br J Pharmacol Chemother. 2010; 2(3):189-206. PMC: 1509780. DOI: 10.1111/j.1476-5381.1947.tb00336.x. View

20.

Chhajlani V, Wikberg J . Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett. 1992; 309(3):417-20. DOI: 10.1016/0014-5793(92)80820-7. View