Synthesis and pharmacology of α/β3-peptides based on the melanocortin agonist Ac-His-d Phe-Arg-Trp-NH2 sequence

Anamika Singh; Srinivasa R. Tala; Viktor Flores; Katie Freeman; Carrie Haskell-Luevano

doi:10.1021/acsmedchemlett.5b00053

Synthesis and pharmacology of α/β³-peptides based on the melanocortin agonist Ac-His-d Phe-Arg-Trp-NH₂ sequence

Anamika Singh
, Srinivasa R. Tala
, Viktor Flores
, Katie Freeman
, Carrie Haskell-Luevano

Medicinal Chemistry

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

25 Scopus citations

Abstract

The melanocortin-3 and -4 receptors are expressed in the brain and play key roles in regulating feeding behavior, metabolism, and energy homeostasis. In the present study, incorporation of β³-amino acids into a melanocortin tetrapeptide template was investigated. Four linear α/β³-hybrid tetrapeptides were designed with the modifications at the Phe, Arg, and Trp residues in the agonist sequence Ac-His-dPhe-Arg-Trp-NH₂. The most potent mouse melanocortin-4 receptor (mMC4R) agonist, Ac-His-dPhe-Arg-β³hTrp-NH₂ (8) showed 35-fold selectivity versus the mMC3R. The study presented here has identified a new template with heterogeneous backbone for designing potent and selective melanocortin receptor ligands.

Original language	English (US)
Pages (from-to)	568-572
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	6
Issue number	5
DOIs	https://doi.org/10.1021/acsmedchemlett.5b00053
State	Published - May 14 2015

Bibliographical note

Publisher Copyright:
© 2015 American Chemical Society.

Keywords

peptidomimetics
α/β-peptides
β-amino acids

Publisher link

10.1021/acsmedchemlett.5b00053

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Cite this

@article{b0aff86a7b584fa4a1d1371f7fb4cee6,

title = "Synthesis and pharmacology of α/β3-peptides based on the melanocortin agonist Ac-His-d Phe-Arg-Trp-NH2 sequence",

abstract = "The melanocortin-3 and -4 receptors are expressed in the brain and play key roles in regulating feeding behavior, metabolism, and energy homeostasis. In the present study, incorporation of β3-amino acids into a melanocortin tetrapeptide template was investigated. Four linear α/β3-hybrid tetrapeptides were designed with the modifications at the Phe, Arg, and Trp residues in the agonist sequence Ac-His-dPhe-Arg-Trp-NH2. The most potent mouse melanocortin-4 receptor (mMC4R) agonist, Ac-His-dPhe-Arg-β3hTrp-NH2 (8) showed 35-fold selectivity versus the mMC3R. The study presented here has identified a new template with heterogeneous backbone for designing potent and selective melanocortin receptor ligands.",

keywords = "peptidomimetics, α/β-peptides, β-amino acids",

author = "Anamika Singh and Tala, \{Srinivasa R.\} and Viktor Flores and Katie Freeman and Carrie Haskell-Luevano",

note = "Publisher Copyright: {\textcopyright} 2015 American Chemical Society.",

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AU - Singh, Anamika

AU - Tala, Srinivasa R.

AU - Flores, Viktor

AU - Freeman, Katie

AU - Haskell-Luevano, Carrie

PY - 2015/5/14

Y1 - 2015/5/14

N2 - The melanocortin-3 and -4 receptors are expressed in the brain and play key roles in regulating feeding behavior, metabolism, and energy homeostasis. In the present study, incorporation of β3-amino acids into a melanocortin tetrapeptide template was investigated. Four linear α/β3-hybrid tetrapeptides were designed with the modifications at the Phe, Arg, and Trp residues in the agonist sequence Ac-His-dPhe-Arg-Trp-NH2. The most potent mouse melanocortin-4 receptor (mMC4R) agonist, Ac-His-dPhe-Arg-β3hTrp-NH2 (8) showed 35-fold selectivity versus the mMC3R. The study presented here has identified a new template with heterogeneous backbone for designing potent and selective melanocortin receptor ligands.

AB - The melanocortin-3 and -4 receptors are expressed in the brain and play key roles in regulating feeding behavior, metabolism, and energy homeostasis. In the present study, incorporation of β3-amino acids into a melanocortin tetrapeptide template was investigated. Four linear α/β3-hybrid tetrapeptides were designed with the modifications at the Phe, Arg, and Trp residues in the agonist sequence Ac-His-dPhe-Arg-Trp-NH2. The most potent mouse melanocortin-4 receptor (mMC4R) agonist, Ac-His-dPhe-Arg-β3hTrp-NH2 (8) showed 35-fold selectivity versus the mMC3R. The study presented here has identified a new template with heterogeneous backbone for designing potent and selective melanocortin receptor ligands.

KW - peptidomimetics

KW - α/β-peptides

KW - β-amino acids

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