Structure activity studies of the melanocortin antagonist SHU9119 modified at the 6, 7, 8, and 9 positions

Carrie Haskell-Luevano; Sejin Lim; Wei Yuan; Roger D. Cone; Victor J. Hruby

doi:10.1016/S0196-9781(99)00167-9

Structure activity studies of the melanocortin antagonist SHU9119 modified at the 6, 7, 8, and 9 positions

Carrie Haskell-Luevano, Sejin Lim, Wei Yuan, Roger D. Cone, Victor J. Hruby

Medicinal Chemistry

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

55 Scopus citations

Abstract

The melanocortin system is involved in the regulation of several diverse physiological pathways, including energy homeostasis. Several synthetic peptide analogs have been designed, synthesized, and pharmacologically characterized at the mouse melanocortin receptor subtypes MC1R, MC3R, MC4R, and MC5R. These peptides incorporate modifications of the melanocortin core amino acids His-Phe-Arg-Trp by using the cyclic lactam templates of the lead structures MTII and SHU9119. Analogs containing DNal(2') at position 7 resulted in partial agonist and antagonistic activities at the mMC3R while possessing full antagonistic activities at the mMC4R. Recently, the melanocortin-5 receptor (MC5R) has been demonstrated to have a role in the regulation of exocrine gland function. This study has characterized the following analogs of SHU9119 that possess antagonist activity at the MC5R: Ac-Nle-c[Asp-(1-Me)His⁶-DNal(2')⁷-Arg-Trp-Lys]-NH₂, pA₂ = 7.1; Ac-Nle- c[Asp-(1-Me)His⁶-DNal(2')⁷-Arg-Nal(2')⁹-Lys]-NH₂, pA₂ = 7.2; and Ac-Nle- c[Asp-Trp⁶-DNal(2')⁷-Arg-Nal(2')⁹-Lys]-NH₂, pA₂ = 6.6. (C) 2000 Elsevier Science Inc.

Original language	English (US)
Pages (from-to)	49-57
Number of pages	9
Journal	Peptides
Volume	21
Issue number	1
DOIs	https://doi.org/10.1016/S0196-9781(99)00167-9
State	Published - Jan 2000

Bibliographical note

Funding Information:
This work was supported in part by U.S. Public Health Service Grants DK17420 (V.J.H.) and AR42415 (R.D.C.). C.H.L. was supported in part by U.S. Public Health Service Grant DK09231 and is a recipient of a Burroughs Wellcome Fund Career Award in the Biomedical Sciences.

Keywords

MTII
Melanocortin antagonists
Melanotropin
SHU9119
α-MSH

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10.1016/S0196-9781(99)00167-9

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title = "Structure activity studies of the melanocortin antagonist SHU9119 modified at the 6, 7, 8, and 9 positions",

abstract = "The melanocortin system is involved in the regulation of several diverse physiological pathways, including energy homeostasis. Several synthetic peptide analogs have been designed, synthesized, and pharmacologically characterized at the mouse melanocortin receptor subtypes MC1R, MC3R, MC4R, and MC5R. These peptides incorporate modifications of the melanocortin core amino acids His-Phe-Arg-Trp by using the cyclic lactam templates of the lead structures MTII and SHU9119. Analogs containing DNal(2') at position 7 resulted in partial agonist and antagonistic activities at the mMC3R while possessing full antagonistic activities at the mMC4R. Recently, the melanocortin-5 receptor (MC5R) has been demonstrated to have a role in the regulation of exocrine gland function. This study has characterized the following analogs of SHU9119 that possess antagonist activity at the MC5R: Ac-Nle-c[Asp-(1-Me)His6-DNal(2')7-Arg-Trp-Lys]-NH2, pA2 = 7.1; Ac-Nle- c[Asp-(1-Me)His6-DNal(2')7-Arg-Nal(2')9-Lys]-NH2, pA2 = 7.2; and Ac-Nle- c[Asp-Trp6-DNal(2')7-Arg-Nal(2')9-Lys]-NH2, pA2 = 6.6. (C) 2000 Elsevier Science Inc.",

keywords = "MTII, Melanocortin antagonists, Melanotropin, SHU9119, α-MSH",

author = "Carrie Haskell-Luevano and Sejin Lim and Wei Yuan and Cone, {Roger D.} and Hruby, {Victor J.}",

note = "Funding Information: This work was supported in part by U.S. Public Health Service Grants DK17420 (V.J.H.) and AR42415 (R.D.C.). C.H.L. was supported in part by U.S. Public Health Service Grant DK09231 and is a recipient of a Burroughs Wellcome Fund Career Award in the Biomedical Sciences. ",

year = "2000",

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doi = "10.1016/S0196-9781(99)00167-9",

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T1 - Structure activity studies of the melanocortin antagonist SHU9119 modified at the 6, 7, 8, and 9 positions

AU - Haskell-Luevano, Carrie

AU - Lim, Sejin

AU - Yuan, Wei

AU - Cone, Roger D.

AU - Hruby, Victor J.

N1 - Funding Information: This work was supported in part by U.S. Public Health Service Grants DK17420 (V.J.H.) and AR42415 (R.D.C.). C.H.L. was supported in part by U.S. Public Health Service Grant DK09231 and is a recipient of a Burroughs Wellcome Fund Career Award in the Biomedical Sciences.

PY - 2000/1

Y1 - 2000/1

N2 - The melanocortin system is involved in the regulation of several diverse physiological pathways, including energy homeostasis. Several synthetic peptide analogs have been designed, synthesized, and pharmacologically characterized at the mouse melanocortin receptor subtypes MC1R, MC3R, MC4R, and MC5R. These peptides incorporate modifications of the melanocortin core amino acids His-Phe-Arg-Trp by using the cyclic lactam templates of the lead structures MTII and SHU9119. Analogs containing DNal(2') at position 7 resulted in partial agonist and antagonistic activities at the mMC3R while possessing full antagonistic activities at the mMC4R. Recently, the melanocortin-5 receptor (MC5R) has been demonstrated to have a role in the regulation of exocrine gland function. This study has characterized the following analogs of SHU9119 that possess antagonist activity at the MC5R: Ac-Nle-c[Asp-(1-Me)His6-DNal(2')7-Arg-Trp-Lys]-NH2, pA2 = 7.1; Ac-Nle- c[Asp-(1-Me)His6-DNal(2')7-Arg-Nal(2')9-Lys]-NH2, pA2 = 7.2; and Ac-Nle- c[Asp-Trp6-DNal(2')7-Arg-Nal(2')9-Lys]-NH2, pA2 = 6.6. (C) 2000 Elsevier Science Inc.

AB - The melanocortin system is involved in the regulation of several diverse physiological pathways, including energy homeostasis. Several synthetic peptide analogs have been designed, synthesized, and pharmacologically characterized at the mouse melanocortin receptor subtypes MC1R, MC3R, MC4R, and MC5R. These peptides incorporate modifications of the melanocortin core amino acids His-Phe-Arg-Trp by using the cyclic lactam templates of the lead structures MTII and SHU9119. Analogs containing DNal(2') at position 7 resulted in partial agonist and antagonistic activities at the mMC3R while possessing full antagonistic activities at the mMC4R. Recently, the melanocortin-5 receptor (MC5R) has been demonstrated to have a role in the regulation of exocrine gland function. This study has characterized the following analogs of SHU9119 that possess antagonist activity at the MC5R: Ac-Nle-c[Asp-(1-Me)His6-DNal(2')7-Arg-Trp-Lys]-NH2, pA2 = 7.1; Ac-Nle- c[Asp-(1-Me)His6-DNal(2')7-Arg-Nal(2')9-Lys]-NH2, pA2 = 7.2; and Ac-Nle- c[Asp-Trp6-DNal(2')7-Arg-Nal(2')9-Lys]-NH2, pA2 = 6.6. (C) 2000 Elsevier Science Inc.

KW - MTII

KW - Melanocortin antagonists

KW - Melanotropin

KW - SHU9119

KW - α-MSH

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DO - 10.1016/S0196-9781(99)00167-9

M3 - Article

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AN - SCOPUS:0033998015

SN - 0196-9781

VL - 21

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EP - 57

JO - Peptides

JF - Peptides

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ER -

Structure activity studies of the melanocortin antagonist SHU9119 modified at the 6, 7, 8, and 9 positions

Abstract

Bibliographical note

Keywords

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