Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa1-Arg-(pI)DPhe-Xaa4-NH2

Skye R. Doering; Katie T. Freeman; Sathya M. Schnell; Erica M. Haslach; Marvin Dirain; Ginamarie Debevec; Phaedra Geer; Radleigh Santos; Marc A. Giulianotti; Clemencia Pinilla; Jon R. Appel; Robert Charles Speth; Richard A. Houghten; Carrie Haskell-Luevano

doi:10.1021/acs.jmedchem.7b00301

Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa1-Arg-(pI)DPhe-Xaa4-NH2

Skye R. Doering
, Katie T. Freeman
, Sathya M. Schnell
, Erica M. Haslach
, Marvin Dirain
, Ginamarie Debevec
, Phaedra Geer
, Radleigh Santos
, Marc A. Giulianotti
, Clemencia Pinilla
, Jon R. Appel
, Robert Charles Speth
, Richard A. Houghten
, Carrie Haskell-Luevano

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

15 Scopus citations

Abstract

The centrally expressed melanocortin-3 and -4 receptors (MC3R/MC4R) have been studied as possible targets for weight management therapies, with a preponderance of studies focusing on the MC4R. Herein, a novel tetrapeptide scaffold [Ac-Xaa ¹ -Arg-(pI)DPhe-Xaa ⁴ -NH ₂ ] is reported. The scaffold was derived from results obtained from a MC3R mixture-based positional scanning campaign. From these results, a set of 48 tetrapeptides were designed and pharmacologically characterized at the mouse melanocortin-1, -3, -4, and -5 receptors. This resulted in the serendipitous discovery of nine compounds that were MC3R agonists (EC ₅₀ < 1000 nM) and MC4R antagonists (5.7 < pA ₂ < 7.8). The three most potent MC3R agonists, 18 [Ac-Arg-Arg-(pI)DPhe-Tic-NH ₂ ], 1 [Ac-His-Arg-(pI)DPhe-Tic-NH ₂ ], and 41 [Ac-Arg-Arg-(pI)DPhe-DNal(2′)-NH ₂ ] were more potent (EC ₅₀ < 73 nM) than the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH ₂ . This template contains a sequentially reversed “Arg-(pI)DPhe” motif with respect to the classical “Phe-Arg” melanocortin signaling motif, which results in pharmacology that is first-in-class for the central melanocortin receptors.

Original language	American English
Pages (from-to)	4342-4357
Number of pages	16
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	10
DOIs	https://doi.org/10.1021/acs.jmedchem.7b00301
State	Published - May 25 2017

Bibliographical note

Publisher Copyright:
© 2017 American Chemical Society.

Funding

We acknowledge Anamika Singh, Srinivasa Tala, Stacey Wilber, Mark Ericson, Katlyn Fleming, Cody Lensing, and Danielle Adank for their aid in the preparation of this manuscript. This work was supported in part by NIH R01 grant R01DK091906 (C.H.L.), and RO1DA031370 (R.A.H.), the State of Florida, Executive Office of the Governor’s Office of Tourism, Trade, and Economic Development (R.A.H.), and a Pilot Award from the Translational Technologies Component of the Georgetown, Howard Universities Center for Clinical and Translational Science, UL1TR000101 (R.C.S.), and NIH HL-113905 (R.C.S.)

Funders	Funder number
Executive Office of the Governor’s Office of Tourism, Trade, and Economic Development
State of Florida
National Institutes of Health	R01DK091906, RO1DA031370
National Center for Advancing Translational Sciences	UL1TR000101
Georgetown-Howard Universities Center for Clinical and Translational Science	HL-113905

ASJC Scopus Subject Areas

Molecular Medicine
Drug Discovery

Keywords

Amino Acid Sequence
Animals
Receptor, Melanocortin, Type 3/agonists
Mice
Oligopeptides/chemistry
Peptide Library
Drug Discovery
Receptor, Melanocortin, Type 4/antagonists & inhibitors

Disciplines

Chemistry
Mathematics
Medicinal-Pharmaceutical Chemistry
Physical Sciences and Mathematics

Access to Document

10.1021/acs.jmedchem.7b00301

Cite this

Doering, S. R., Freeman, K. T., Schnell, S. M., Haslach, E. M., Dirain, M., Debevec, G., Geer, P., Santos, R., Giulianotti, M. A., Pinilla, C., Appel, J. R., Speth, R. C., Houghten, R. A., & Haskell-Luevano, C. (2017). Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa1-Arg-(pI)DPhe-Xaa4-NH2. Journal of Medicinal Chemistry, 60(10), 4342-4357. https://doi.org/10.1021/acs.jmedchem.7b00301

Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa1-Arg-(pI)DPhe-Xaa4-NH2. / Doering, Skye R.; Freeman, Katie T.; Schnell, Sathya M. et al.
In: Journal of Medicinal Chemistry, Vol. 60, No. 10, 25.05.2017, p. 4342-4357.

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

Doering, SR, Freeman, KT, Schnell, SM, Haslach, EM, Dirain, M, Debevec, G, Geer, P, Santos, R, Giulianotti, MA, Pinilla, C, Appel, JR, Speth, RC, Houghten, RA & Haskell-Luevano, C 2017, 'Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa1-Arg-(pI)DPhe-Xaa4-NH2', Journal of Medicinal Chemistry, vol. 60, no. 10, pp. 4342-4357. https://doi.org/10.1021/acs.jmedchem.7b00301

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title = "Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa1-Arg-(pI)DPhe-Xaa4-NH2",

abstract = " The centrally expressed melanocortin-3 and -4 receptors (MC3R/MC4R) have been studied as possible targets for weight management therapies, with a preponderance of studies focusing on the MC4R. Herein, a novel tetrapeptide scaffold [Ac-Xaa 1 -Arg-(pI)DPhe-Xaa 4 -NH 2 ] is reported. The scaffold was derived from results obtained from a MC3R mixture-based positional scanning campaign. From these results, a set of 48 tetrapeptides were designed and pharmacologically characterized at the mouse melanocortin-1, -3, -4, and -5 receptors. This resulted in the serendipitous discovery of nine compounds that were MC3R agonists (EC 50 < 1000 nM) and MC4R antagonists (5.7 < pA 2 < 7.8). The three most potent MC3R agonists, 18 [Ac-Arg-Arg-(pI)DPhe-Tic-NH 2 ], 1 [Ac-His-Arg-(pI)DPhe-Tic-NH 2 ], and 41 [Ac-Arg-Arg-(pI)DPhe-DNal(2′)-NH 2 ] were more potent (EC 50 < 73 nM) than the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH 2 . This template contains a sequentially reversed “Arg-(pI)DPhe” motif with respect to the classical “Phe-Arg” melanocortin signaling motif, which results in pharmacology that is first-in-class for the central melanocortin receptors.",

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AU - Doering, Skye R.

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AU - Giulianotti, Marc A.

AU - Pinilla, Clemencia

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AU - Haskell-Luevano, Carrie

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Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa1-Arg-(pI)DPhe-Xaa4-NH2

Abstract

Bibliographical note

Funding

ASJC Scopus Subject Areas

Keywords

Disciplines

Access to Document

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