Cyclic lactam hybrid α-MSH/Agouti-related protein (AGRP) analogues with nanomolar range binding affinities at the human melanocortin receptors

Alexander V. Mayorov; Minying Cai; Erin S. Palmer; Dustin K. Tanaka; James P. Cain; Matthew M. Dedek; Bahar Tan; Dev Trivedi; Victor J. Hruby

doi:10.1016/j.bmcl.2011.03.019

Cyclic lactam hybrid α-MSH/Agouti-related protein (AGRP) analogues with nanomolar range binding affinities at the human melanocortin receptors

Alexander V. Mayorov, Minying Cai, Erin S. Palmer, Dustin K. Tanaka, James P. Cain, Matthew M. Dedek, Bahar Tan, Dev Trivedi, Victor J. Hruby

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

6 Scopus citations

Abstract

A novel hybrid melanocortin pharmacophore was designed based on the topographical similarities between the pharmacophores of Agouti related protein (AGRP) an endogenous melanocortin antagonist, and α-melanocyte-stimulating hormone (α-MSH), an endogenous melanocortin agonist. When employed in two different 23-membered macrocyclic lactam peptide templates, the designed hybrid AGRP/MSH pharmacophore yielded non-competitive ligands with nanomolar range binding affinities. The topography-based pharmacophore hybridization strategy will prove useful in development of unique non-competitive melanocortin receptor modulators.

Original language	English (US)
Pages (from-to)	3099-3102
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2011.03.019
State	Published - May 15 2011

Keywords

Agouti-related protein
Human melanocortin receptors
Hybrid pharmacophore
Macrocyclic peptide
α-MSH

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.2011.03.019

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Mayorov, A. V., Cai, M., Palmer, E. S., Tanaka, D. K., Cain, J. P., Dedek, M. M., Tan, B., Trivedi, D., & Hruby, V. J. (2011). Cyclic lactam hybrid α-MSH/Agouti-related protein (AGRP) analogues with nanomolar range binding affinities at the human melanocortin receptors. Bioorganic and Medicinal Chemistry Letters, 21(10), 3099-3102. https://doi.org/10.1016/j.bmcl.2011.03.019

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title = "Cyclic lactam hybrid α-MSH/Agouti-related protein (AGRP) analogues with nanomolar range binding affinities at the human melanocortin receptors",

abstract = "A novel hybrid melanocortin pharmacophore was designed based on the topographical similarities between the pharmacophores of Agouti related protein (AGRP) an endogenous melanocortin antagonist, and α-melanocyte-stimulating hormone (α-MSH), an endogenous melanocortin agonist. When employed in two different 23-membered macrocyclic lactam peptide templates, the designed hybrid AGRP/MSH pharmacophore yielded non-competitive ligands with nanomolar range binding affinities. The topography-based pharmacophore hybridization strategy will prove useful in development of unique non-competitive melanocortin receptor modulators.",

keywords = "Agouti-related protein, Human melanocortin receptors, Hybrid pharmacophore, Macrocyclic peptide, α-MSH",

author = "Mayorov, {Alexander V.} and Minying Cai and Palmer, {Erin S.} and Tanaka, {Dustin K.} and Cain, {James P.} and Dedek, {Matthew M.} and Bahar Tan and Dev Trivedi and Hruby, {Victor J.}",

note = "Funding Information: This work was supported 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.",

year = "2011",

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doi = "10.1016/j.bmcl.2011.03.019",

language = "English (US)",

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AU - Mayorov, Alexander V.

AU - Cai, Minying

AU - Palmer, Erin S.

AU - Tanaka, Dustin K.

AU - Cain, James P.

AU - Dedek, Matthew M.

AU - Tan, Bahar

AU - Trivedi, Dev

AU - Hruby, Victor J.

N1 - Funding Information: This work was supported 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 - 2011/5/15

Y1 - 2011/5/15

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AB - A novel hybrid melanocortin pharmacophore was designed based on the topographical similarities between the pharmacophores of Agouti related protein (AGRP) an endogenous melanocortin antagonist, and α-melanocyte-stimulating hormone (α-MSH), an endogenous melanocortin agonist. When employed in two different 23-membered macrocyclic lactam peptide templates, the designed hybrid AGRP/MSH pharmacophore yielded non-competitive ligands with nanomolar range binding affinities. The topography-based pharmacophore hybridization strategy will prove useful in development of unique non-competitive melanocortin receptor modulators.

KW - Agouti-related protein

KW - Human melanocortin receptors

KW - Hybrid pharmacophore

KW - Macrocyclic peptide

KW - α-MSH

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Cyclic lactam hybrid α-MSH/Agouti-related protein (AGRP) analogues with nanomolar range binding affinities at the human melanocortin receptors

Abstract

Keywords

ASJC Scopus subject areas

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