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ACS Med Chem Lett. 2015 Apr 8;6(5):568-72. doi: 10.1021/acsmedchemlett.5b00053. eCollection 2015 May 14.

Synthesis and Pharmacology of α/β(3)-Peptides Based on the Melanocortin Agonist Ac-His-dPhe-Arg-Trp-NH2 Sequence.

Author information

1
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55455, United States ; Department of Pharmacodynamics, College of Pharmacy, University of Florida , Gainesville, Florida 32610, United States.
2
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55455, United States.
3
Department of Pharmacodynamics, College of Pharmacy, University of Florida , Gainesville, Florida 32610, United States.

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 β(3)-amino acids into a melanocortin tetrapeptide template was investigated. Four linear α/β(3)-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-β(3)hTrp-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/β3-peptides; β-amino acids

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