Synthesis and Pharmacology of alpha/beta(3)-Peptides Based on the Melanocortin Agonist Ac-His-DPhe-Arg-Trp-NH2 Sequence

摘要

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 beta(3)-amino acids into a melanocortin tetrapeptide template was investigated. Four linear alpha/beta(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-beta(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.