| Autor: |
Zhou, Yang, Mowlazadeh Haghighi, Saghar, Sawyer, Jonathon R., Hruby, Victor J., Cai, Minying |
| Zdroj: |
Journal of Medicinal Chemistry; May 2023, Vol. 66 Issue: 10 p6715-6724, 10p |
| Abstrakt: |
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-NH2. With these conformational constraints, peptide 1(Ac-His-d-Phe-Arg-Aia) shows improved selectivity at hMC1R, with an EC50of 11.2 nM for hMC1R and at least 15-fold selectivity compared to other MCR subtypes. Peptide 3(Ac-His-pCF3-d-Phe-Arg-Aia) is a potent and selective hMC4R agonist with an EC50of 4.1 nM at hMC4R and at least ninefold selectivity. Molecular docking studies reveal that the Ψ and χ angle constraints force the C-terminal Aia residue to flip and interact with TM6 and TM7, a feature that we hypothesize leads to the receptor subtype selectivity. |
| Databáze: |
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