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.",

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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.

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Y1 - 2011/5/15

N2 - 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.

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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AN - SCOPUS:79955564940

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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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