Azepinone-containing tetrapeptide analogues of melanotropin lead to selective h MC4R agonists and h MC5R antagonist

Olivier Van Der Poorten; Krisztina Fehér; Koen Buysse; Debby Feytens; Ioanna Zoi; Steven D. Schwartz; José C. Martins; Dirk Tourwé; Minying Cai; Victor J. Hruby; Steven Ballet

doi:10.1021/ml500436s

Azepinone-containing tetrapeptide analogues of melanotropin lead to selective h MC4R agonists and h MC5R antagonist

Olivier Van Der Poorten, Krisztina Fehér, Koen Buysse, Debby Feytens, Ioanna Zoi, Steven D. Schwartz, José C. Martins, Dirk Tourwé, Minying Cai, Victor J. Hruby, Steven Ballet

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

11 Scopus citations

Abstract

To address the need for highly potent, metabolically stable, and selective agonists, antagonists, and inverse agonists at the melanocortin receptor subtypes, conformationally constrained indolo- and benzazepinone residues were inserted into the α-MSH pharmacophore, His⁶-Phe⁷-Arg⁸-Trp⁹-domain. Replacement of His⁶ by an aminoindoloazepinone (Aia) or aminobenzazepinone (Aba) moiety led to hMC4R and hMC5R selective agonist and antagonist ligands, respectively (tetrapeptides 1 to 3 and 4, respectively). In peptides 1 to 3 and depending on the para-substituent of the d-Phe residue in position 2, the activity goes from allosteric partial agonism (1, R = H) to allosteric full agonism (2, R = F) and finally allosteric partial agonism (3, R = Br).

Original language	English (US)
Pages (from-to)	192-197
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	6
Issue number	2
DOIs	https://doi.org/10.1021/ml500436s
State	Published - Feb 12 2015

Keywords

Melanocortin ligands
allosteric hMC4R ligands
constrained aminoazepinones
fluorine peptidomimetics
hMC4R and hMC5R molecular modeling and ligand docking

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml500436s

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title = "Azepinone-containing tetrapeptide analogues of melanotropin lead to selective h MC4R agonists and h MC5R antagonist",

abstract = "To address the need for highly potent, metabolically stable, and selective agonists, antagonists, and inverse agonists at the melanocortin receptor subtypes, conformationally constrained indolo- and benzazepinone residues were inserted into the α-MSH pharmacophore, His6-Phe7-Arg8-Trp9-domain. Replacement of His6 by an aminoindoloazepinone (Aia) or aminobenzazepinone (Aba) moiety led to hMC4R and hMC5R selective agonist and antagonist ligands, respectively (tetrapeptides 1 to 3 and 4, respectively). In peptides 1 to 3 and depending on the para-substituent of the d-Phe residue in position 2, the activity goes from allosteric partial agonism (1, R = H) to allosteric full agonism (2, R = F) and finally allosteric partial agonism (3, R = Br).",

keywords = "Melanocortin ligands, allosteric hMC4R ligands, constrained aminoazepinones, fluorine peptidomimetics, hMC4R and hMC5R molecular modeling and ligand docking",

author = "{Van Der Poorten}, Olivier and Krisztina Feh{\'e}r and Koen Buysse and Debby Feytens and Ioanna Zoi and Schwartz, {Steven D.} and Martins, {Jos{\'e} C.} and Dirk Tourw{\'e} and Minying Cai and Hruby, {Victor J.} and Steven Ballet",

note = "Publisher Copyright: {\textcopyright} 2014 American Chemical Society.",

year = "2015",

month = feb,

day = "12",

doi = "10.1021/ml500436s",

language = "English (US)",

volume = "6",

pages = "192--197",

journal = "ACS Medicinal Chemistry Letters",

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T1 - Azepinone-containing tetrapeptide analogues of melanotropin lead to selective h MC4R agonists and h MC5R antagonist

AU - Van Der Poorten, Olivier

AU - Fehér, Krisztina

AU - Buysse, Koen

AU - Feytens, Debby

AU - Zoi, Ioanna

AU - Schwartz, Steven D.

AU - Martins, José C.

AU - Tourwé, Dirk

AU - Cai, Minying

AU - Hruby, Victor J.

AU - Ballet, Steven

PY - 2015/2/12

Y1 - 2015/2/12

N2 - To address the need for highly potent, metabolically stable, and selective agonists, antagonists, and inverse agonists at the melanocortin receptor subtypes, conformationally constrained indolo- and benzazepinone residues were inserted into the α-MSH pharmacophore, His6-Phe7-Arg8-Trp9-domain. Replacement of His6 by an aminoindoloazepinone (Aia) or aminobenzazepinone (Aba) moiety led to hMC4R and hMC5R selective agonist and antagonist ligands, respectively (tetrapeptides 1 to 3 and 4, respectively). In peptides 1 to 3 and depending on the para-substituent of the d-Phe residue in position 2, the activity goes from allosteric partial agonism (1, R = H) to allosteric full agonism (2, R = F) and finally allosteric partial agonism (3, R = Br).

AB - To address the need for highly potent, metabolically stable, and selective agonists, antagonists, and inverse agonists at the melanocortin receptor subtypes, conformationally constrained indolo- and benzazepinone residues were inserted into the α-MSH pharmacophore, His6-Phe7-Arg8-Trp9-domain. Replacement of His6 by an aminoindoloazepinone (Aia) or aminobenzazepinone (Aba) moiety led to hMC4R and hMC5R selective agonist and antagonist ligands, respectively (tetrapeptides 1 to 3 and 4, respectively). In peptides 1 to 3 and depending on the para-substituent of the d-Phe residue in position 2, the activity goes from allosteric partial agonism (1, R = H) to allosteric full agonism (2, R = F) and finally allosteric partial agonism (3, R = Br).

KW - Melanocortin ligands

KW - allosteric hMC4R ligands

KW - constrained aminoazepinones

KW - fluorine peptidomimetics

KW - hMC4R and hMC5R molecular modeling and ligand docking

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Azepinone-containing tetrapeptide analogues of melanotropin lead to selective h MC4R agonists and h MC5R antagonist

Abstract

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