Novel selective human melanocortin-3 receptor ligands: Use of the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffold

Steven Ballet; Alexander V. Mayorov; Minying Cai; Dagmara Tymecka; Kevin B. Chandler; Erin S. Palmer; Karolien Van Rompaey; Aleksandra Misicka; Dirk Tourwé; Victor J Hruby

doi:10.1016/j.bmcl.2007.02.020

Novel selective human melanocortin-3 receptor ligands: Use of the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffold

Steven Ballet, Alexander V. Mayorov, Minying Cai, Dagmara Tymecka, Kevin B. Chandler, Erin S. Palmer, Karolien Van Rompaey, Aleksandra Misicka, Dirk Tourwé, Victor J Hruby

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

29 Scopus citations

Abstract

In search of new selective antagonists and/or agonists for the human melanocortin receptor subtypes hMC1R to hMC5R to elucidate the specific biological roles of each GPCR, we modified the structures of the superagonist MT-II (Ac-Nle-c[Asp-His-d-Phe-Arg-Trp-Lys]-NH₂) and the hMC3R/hMC4R antagonist SHU9119 (Ac-Nle-c[Asp-His-d-Nal(2′)-Arg-Trp-Lys]-NH₂) by replacing the His-d-Phe and His-d-Nal(2′) fragments in MT-II and SHU9119, respectively, with Aba-Xxx (4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one-Xxx) dipeptidomimetics (Xxx = d-Phe/pCl-d-Phe/d-Nal(2′)). Employment of the Aba mimetic yielded novel selective high affinity hMC3R and hMC3R/hMC5R antagonists.

Original language	English (US)
Pages (from-to)	2492-2498
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	17
Issue number	9
DOIs	https://doi.org/10.1016/j.bmcl.2007.02.020
State	Published - May 1 2007

Keywords

4-Amino-1,2,4,5-tetrahydro-2-benzazepin-3-ones
Conformational restrictions
Cyclic lactam analogues
Human melanocortin receptors
hMC3R/hMC5R antagonists

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2007.02.020

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Ballet, S., Mayorov, A. V., Cai, M., Tymecka, D., Chandler, K. B., Palmer, E. S., Rompaey, K. V., Misicka, A., Tourwé, D., & Hruby, V. J. (2007). Novel selective human melanocortin-3 receptor ligands: Use of the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffold. Bioorganic and Medicinal Chemistry Letters, 17(9), 2492-2498. https://doi.org/10.1016/j.bmcl.2007.02.020

Ballet, S, Mayorov, AV, Cai, M, Tymecka, D, Chandler, KB, Palmer, ES, Rompaey, KV, Misicka, A, Tourwé, D & Hruby, VJ 2007, 'Novel selective human melanocortin-3 receptor ligands: Use of the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffold', Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 9, pp. 2492-2498. https://doi.org/10.1016/j.bmcl.2007.02.020

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title = "Novel selective human melanocortin-3 receptor ligands: Use of the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffold",

abstract = "In search of new selective antagonists and/or agonists for the human melanocortin receptor subtypes hMC1R to hMC5R to elucidate the specific biological roles of each GPCR, we modified the structures of the superagonist MT-II (Ac-Nle-c[Asp-His-d-Phe-Arg-Trp-Lys]-NH2) and the hMC3R/hMC4R antagonist SHU9119 (Ac-Nle-c[Asp-His-d-Nal(2′)-Arg-Trp-Lys]-NH2) by replacing the His-d-Phe and His-d-Nal(2′) fragments in MT-II and SHU9119, respectively, with Aba-Xxx (4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one-Xxx) dipeptidomimetics (Xxx = d-Phe/pCl-d-Phe/d-Nal(2′)). Employment of the Aba mimetic yielded novel selective high affinity hMC3R and hMC3R/hMC5R antagonists.",

keywords = "4-Amino-1,2,4,5-tetrahydro-2-benzazepin-3-ones, Conformational restrictions, Cyclic lactam analogues, Human melanocortin receptors, hMC3R/hMC5R antagonists",

author = "Steven Ballet and Mayorov, {Alexander V.} and Minying Cai and Dagmara Tymecka and Chandler, {Kevin B.} and Palmer, {Erin S.} and Rompaey, {Karolien Van} and Aleksandra Misicka and Dirk Tourw{\'e} and Hruby, {Victor J}",

note = "Funding Information: This work was supported by the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT Vlaanderen), and by grants from the U.S. Public Health Service, National Institutes of Health DK-17420 and DA-06284. The opinions expressed are those of the authors and not necessarily those of the USPHS.",

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doi = "10.1016/j.bmcl.2007.02.020",

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T1 - Novel selective human melanocortin-3 receptor ligands

T2 - Use of the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffold

AU - Ballet, Steven

AU - Mayorov, Alexander V.

AU - Cai, Minying

AU - Tymecka, Dagmara

AU - Chandler, Kevin B.

AU - Palmer, Erin S.

AU - Rompaey, Karolien Van

AU - Misicka, Aleksandra

AU - Tourwé, Dirk

AU - Hruby, Victor J

N1 - Funding Information: This work was supported by the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT Vlaanderen), and by grants from the U.S. Public Health Service, National Institutes of Health DK-17420 and DA-06284. The opinions expressed are those of the authors and not necessarily those of the USPHS.

PY - 2007/5/1

Y1 - 2007/5/1

N2 - In search of new selective antagonists and/or agonists for the human melanocortin receptor subtypes hMC1R to hMC5R to elucidate the specific biological roles of each GPCR, we modified the structures of the superagonist MT-II (Ac-Nle-c[Asp-His-d-Phe-Arg-Trp-Lys]-NH2) and the hMC3R/hMC4R antagonist SHU9119 (Ac-Nle-c[Asp-His-d-Nal(2′)-Arg-Trp-Lys]-NH2) by replacing the His-d-Phe and His-d-Nal(2′) fragments in MT-II and SHU9119, respectively, with Aba-Xxx (4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one-Xxx) dipeptidomimetics (Xxx = d-Phe/pCl-d-Phe/d-Nal(2′)). Employment of the Aba mimetic yielded novel selective high affinity hMC3R and hMC3R/hMC5R antagonists.

AB - In search of new selective antagonists and/or agonists for the human melanocortin receptor subtypes hMC1R to hMC5R to elucidate the specific biological roles of each GPCR, we modified the structures of the superagonist MT-II (Ac-Nle-c[Asp-His-d-Phe-Arg-Trp-Lys]-NH2) and the hMC3R/hMC4R antagonist SHU9119 (Ac-Nle-c[Asp-His-d-Nal(2′)-Arg-Trp-Lys]-NH2) by replacing the His-d-Phe and His-d-Nal(2′) fragments in MT-II and SHU9119, respectively, with Aba-Xxx (4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one-Xxx) dipeptidomimetics (Xxx = d-Phe/pCl-d-Phe/d-Nal(2′)). Employment of the Aba mimetic yielded novel selective high affinity hMC3R and hMC3R/hMC5R antagonists.

KW - 4-Amino-1,2,4,5-tetrahydro-2-benzazepin-3-ones

KW - Conformational restrictions

KW - Cyclic lactam analogues

KW - Human melanocortin receptors

KW - hMC3R/hMC5R antagonists

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SN - 0960-894X

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EP - 2498

JO - Bioorganic and Medicinal Chemistry Letters

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Novel selective human melanocortin-3 receptor ligands: Use of the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffold

Abstract

Keywords

ASJC Scopus subject areas

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