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Synthesis and Pharmacology of α/β3‑Peptides Based on the Melanocortin Agonist Ac-His‑dPhe-Arg-Trp-NH2 Sequence

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journal contribution
posted on 14.05.2015, 00:00 by Anamika Singh, Srinivasa R. Tala, Viktor Flores, Katie Freeman, Carrie Haskell-Luevano
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.