Truncation studies of α-melanotropin peptides identify tripeptide analogues exhibiting prolonged agonist bioactivity

Carrie Haskell-Luevano; Tomi K. Sawyer; Siska Hendrata; Cheryl North; Laila Panahinia; Martha Stum; Douglas J. Staples; Anna M. De Lauro Castrucci; Mac E. Hadley; Victor J. Hruby

doi:10.1016/S0196-9781(96)00141-6

Truncation studies of α-melanotropin peptides identify tripeptide analogues exhibiting prolonged agonist bioactivity

Carrie Haskell-Luevano, Tomi K. Sawyer, Siska Hendrata, Cheryl North, Laila Panahinia, Martha Stum, Douglas J. Staples, Anna M. De Lauro Castrucci, Mac E. Hadley, Victor J. Hruby

Medicinal Chemistry

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Abstract

Systematic analysis of fragment derivatives of the superpotent α-MSH analogue, Ac-Ser-Tyr-Ser-Nle⁴-Glu-His-DPhe⁷-Arg-Trp-Gly-Lys-Pro-Val-NH₂ (NDP-MSH), led to the discovery of tripeptide agonists possessing prolonged bioactivity in the frog skin assay. Of particular significance to this discovery was Ac-DPhe-Arg-DTrp-NH₂, which was the most potent tripeptide in this series exhibiting sustained melanotropic activity. Different pharmacophore models appear to exist that are dependent on the substructure and stereochemistry of the MSH(6-9) 'active site.' The tripeptides Ac-DPhe-Arg-Trp-NH₂, Ac-DPhe-Arg-DTrp-NH₂, and Ac-DPhe-DArg-Trp-NH₂ stereochemical combinations require only Phe⁷-Xaa⁸-Trp⁹, whereas Ac-DPhe-DArg-DTrp-NH₂, Ac-Phe-Arg-DTrp-NH₂, and Ac-Phe-Arg-Trp-NH₂ additionally require His⁶ for minimal biological activity. Ac-DPhe-Arg-DTrp-NH₂ represents a novel prototype lead for the development of MSH-based peptidomimetic agonists.

Original language	English (US)
Pages (from-to)	995-1002
Number of pages	8
Journal	Peptides
Volume	17
Issue number	6
DOIs	https://doi.org/10.1016/S0196-9781(96)00141-6
State	Published - 1996

Bibliographical note

Funding Information:
This work was supported by grants from the U.S. Public Health Service, DK 17420 (V.J.H.) and DK0923 1 (C.H.L.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the USPHS.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

Ac-[Nle,DPhe]α-MSH
NDP-MSH
melanotrop in pharmacophore
melanotropin
α-MSH
α-melanocyte stimulating hormone

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@article{70ec7eb366ef4d2ba08ab6b219ef58a4,

title = "Truncation studies of α-melanotropin peptides identify tripeptide analogues exhibiting prolonged agonist bioactivity",

abstract = "Systematic analysis of fragment derivatives of the superpotent α-MSH analogue, Ac-Ser-Tyr-Ser-Nle4-Glu-His-DPhe7-Arg-Trp-Gly-Lys-Pro-Val-NH2 (NDP-MSH), led to the discovery of tripeptide agonists possessing prolonged bioactivity in the frog skin assay. Of particular significance to this discovery was Ac-DPhe-Arg-DTrp-NH2, which was the most potent tripeptide in this series exhibiting sustained melanotropic activity. Different pharmacophore models appear to exist that are dependent on the substructure and stereochemistry of the MSH(6-9) 'active site.' The tripeptides Ac-DPhe-Arg-Trp-NH2, Ac-DPhe-Arg-DTrp-NH2, and Ac-DPhe-DArg-Trp-NH2 stereochemical combinations require only Phe7-Xaa8-Trp9, whereas Ac-DPhe-DArg-DTrp-NH2, Ac-Phe-Arg-DTrp-NH2, and Ac-Phe-Arg-Trp-NH2 additionally require His6 for minimal biological activity. Ac-DPhe-Arg-DTrp-NH2 represents a novel prototype lead for the development of MSH-based peptidomimetic agonists.",

keywords = "Ac-[Nle,DPhe]α-MSH, NDP-MSH, melanotrop in pharmacophore, melanotropin, α-MSH, α-melanocyte stimulating hormone",

author = "Carrie Haskell-Luevano and Sawyer, {Tomi K.} and Siska Hendrata and Cheryl North and Laila Panahinia and Martha Stum and Staples, {Douglas J.} and {De Lauro Castrucci}, {Anna M.} and Hadley, {Mac E.} and Hruby, {Victor J.}",

note = "Funding Information: This work was supported by grants from the U.S. Public Health Service, DK 17420 (V.J.H.) and DK0923 1 (C.H.L.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the USPHS. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",

year = "1996",

doi = "10.1016/S0196-9781(96)00141-6",

language = "English (US)",

volume = "17",

pages = "995--1002",

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T1 - Truncation studies of α-melanotropin peptides identify tripeptide analogues exhibiting prolonged agonist bioactivity

AU - Haskell-Luevano, Carrie

AU - Sawyer, Tomi K.

AU - Hendrata, Siska

AU - North, Cheryl

AU - Panahinia, Laila

AU - Stum, Martha

AU - Staples, Douglas J.

AU - De Lauro Castrucci, Anna M.

AU - Hadley, Mac E.

AU - Hruby, Victor J.

N1 - Funding Information: This work was supported by grants from the U.S. Public Health Service, DK 17420 (V.J.H.) and DK0923 1 (C.H.L.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the USPHS. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

PY - 1996

Y1 - 1996

N2 - Systematic analysis of fragment derivatives of the superpotent α-MSH analogue, Ac-Ser-Tyr-Ser-Nle4-Glu-His-DPhe7-Arg-Trp-Gly-Lys-Pro-Val-NH2 (NDP-MSH), led to the discovery of tripeptide agonists possessing prolonged bioactivity in the frog skin assay. Of particular significance to this discovery was Ac-DPhe-Arg-DTrp-NH2, which was the most potent tripeptide in this series exhibiting sustained melanotropic activity. Different pharmacophore models appear to exist that are dependent on the substructure and stereochemistry of the MSH(6-9) 'active site.' The tripeptides Ac-DPhe-Arg-Trp-NH2, Ac-DPhe-Arg-DTrp-NH2, and Ac-DPhe-DArg-Trp-NH2 stereochemical combinations require only Phe7-Xaa8-Trp9, whereas Ac-DPhe-DArg-DTrp-NH2, Ac-Phe-Arg-DTrp-NH2, and Ac-Phe-Arg-Trp-NH2 additionally require His6 for minimal biological activity. Ac-DPhe-Arg-DTrp-NH2 represents a novel prototype lead for the development of MSH-based peptidomimetic agonists.

AB - Systematic analysis of fragment derivatives of the superpotent α-MSH analogue, Ac-Ser-Tyr-Ser-Nle4-Glu-His-DPhe7-Arg-Trp-Gly-Lys-Pro-Val-NH2 (NDP-MSH), led to the discovery of tripeptide agonists possessing prolonged bioactivity in the frog skin assay. Of particular significance to this discovery was Ac-DPhe-Arg-DTrp-NH2, which was the most potent tripeptide in this series exhibiting sustained melanotropic activity. Different pharmacophore models appear to exist that are dependent on the substructure and stereochemistry of the MSH(6-9) 'active site.' The tripeptides Ac-DPhe-Arg-Trp-NH2, Ac-DPhe-Arg-DTrp-NH2, and Ac-DPhe-DArg-Trp-NH2 stereochemical combinations require only Phe7-Xaa8-Trp9, whereas Ac-DPhe-DArg-DTrp-NH2, Ac-Phe-Arg-DTrp-NH2, and Ac-Phe-Arg-Trp-NH2 additionally require His6 for minimal biological activity. Ac-DPhe-Arg-DTrp-NH2 represents a novel prototype lead for the development of MSH-based peptidomimetic agonists.

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KW - α-MSH

KW - α-melanocyte stimulating hormone

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Truncation studies of α-melanotropin peptides identify tripeptide analogues exhibiting prolonged agonist bioactivity

Abstract

Bibliographical note

Keywords

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