Ψ and χ Angle Constrains at the C-Terminus Trp Position of the Melanotropin Tetrapeptide Ac-His-d-Phe-Arg-Trp-NH

Melanocortin receptors (MCRs) are a family of G protein-coupled receptors that regulate important physiological functions. Yet, drug development targeting MCRs is hindered by potential side effects due to a lack of receptor subtype-selective ligands with bioavailability. Here, we report novel synthetic pathways to introduce Ψ and χ angle constraints at the C-terminus Trp position of the nonselective prototype tetrapeptide agonist Ac-His-d-Phe-Arg-Trp-NH