Semi-rigid tripeptide agonists of melanocortin receptors

Andrew R. Ruwe; Leonid Koikov; Zalfa Abdel-Malek; Carrie Haskell-Luevano; Marvin L. Dirain; Federico Portillo; Zhimin Xiang; Matt Wortman; James J. Knittel

doi:10.1016/j.bmcl.2009.07.025

Semi-rigid tripeptide agonists of melanocortin receptors

Andrew R. Ruwe, Leonid Koikov, Zalfa Abdel-Malek, Carrie Haskell-Luevano, Marvin L. Dirain, Federico Portillo, Zhimin Xiang, Matt Wortman, James J. Knittel

Medicinal Chemistry

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Abstract

A series of 30 RCO-HfR-NH₂ derivatives show preference for the mouse MC1R vs MC3-5Rs. trans-4-HOC₆H₄CH{double bond, long}CHCO-HfR-NH₂ (13) [EC₅₀ (nM): MC1R 83, MC3R 20500, MC4R 18130 and MC5R 935; ratio 1:246:217:11] is 11 times more potent than the lead compound LK-394 Ph(CH₂)₃CO-HfR-NH₂ (2) and only 11 times less potent than the native tridecapeptide α-MSH at mMC1R. Differences in conformations of 2 and 13 are discussed.

Original language	English (US)
Pages (from-to)	5176-5181
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	17
DOIs	https://doi.org/10.1016/j.bmcl.2009.07.025
State	Published - Sep 1 2009

Keywords

Conformational analysis
Melanocortin agonists
Melanocortin receptors
Molecular modeling
N-capping
Peptidomimetics

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title = "Semi-rigid tripeptide agonists of melanocortin receptors",

abstract = "A series of 30 RCO-HfR-NH2 derivatives show preference for the mouse MC1R vs MC3-5Rs. trans-4-HOC6H4CH{double bond, long}CHCO-HfR-NH2 (13) [EC50 (nM): MC1R 83, MC3R 20500, MC4R 18130 and MC5R 935; ratio 1:246:217:11] is 11 times more potent than the lead compound LK-394 Ph(CH2)3CO-HfR-NH2 (2) and only 11 times less potent than the native tridecapeptide α-MSH at mMC1R. Differences in conformations of 2 and 13 are discussed.",

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author = "Ruwe, {Andrew R.} and Leonid Koikov and Zalfa Abdel-Malek and Carrie Haskell-Luevano and Dirain, {Marvin L.} and Federico Portillo and Zhimin Xiang and Matt Wortman and Knittel, {James J.}",

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AU - Ruwe, Andrew R.

AU - Koikov, Leonid

AU - Abdel-Malek, Zalfa

AU - Haskell-Luevano, Carrie

AU - Dirain, Marvin L.

AU - Portillo, Federico

AU - Xiang, Zhimin

AU - Wortman, Matt

AU - Knittel, James J.

PY - 2009/9/1

Y1 - 2009/9/1

N2 - A series of 30 RCO-HfR-NH2 derivatives show preference for the mouse MC1R vs MC3-5Rs. trans-4-HOC6H4CH{double bond, long}CHCO-HfR-NH2 (13) [EC50 (nM): MC1R 83, MC3R 20500, MC4R 18130 and MC5R 935; ratio 1:246:217:11] is 11 times more potent than the lead compound LK-394 Ph(CH2)3CO-HfR-NH2 (2) and only 11 times less potent than the native tridecapeptide α-MSH at mMC1R. Differences in conformations of 2 and 13 are discussed.

AB - A series of 30 RCO-HfR-NH2 derivatives show preference for the mouse MC1R vs MC3-5Rs. trans-4-HOC6H4CH{double bond, long}CHCO-HfR-NH2 (13) [EC50 (nM): MC1R 83, MC3R 20500, MC4R 18130 and MC5R 935; ratio 1:246:217:11] is 11 times more potent than the lead compound LK-394 Ph(CH2)3CO-HfR-NH2 (2) and only 11 times less potent than the native tridecapeptide α-MSH at mMC1R. Differences in conformations of 2 and 13 are discussed.

KW - Conformational analysis

KW - Melanocortin agonists

KW - Melanocortin receptors

KW - Molecular modeling

KW - N-capping

KW - Peptidomimetics

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Semi-rigid tripeptide agonists of melanocortin receptors

Abstract

Keywords

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