Structure-Activity Relationship Studies on a Macrocyclic Agouti-Related Protein (AGRP) Scaffold Reveal Agouti Signaling Protein (ASP) Residue Substitutions Maintain Melanocortin-4 Receptor Antagonist Potency and Result in Inverse Agonist Pharmacology at the Melanocortin-5 Receptor
| Autor: | Katie T. Freeman, Sathya M. Schnell, Katlyn A. Fleming, Mark D. Ericson, Carrie Haskell-Luevano |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular Pharmacology Ligands Article 03 medical and health sciences Mice Structure-Activity Relationship 0302 clinical medicine Proopiomelanocortin Melanocortin receptor Drug Discovery Cyclic AMP Inverse agonist Structure–activity relationship Animals Humans Agouti-Related Protein Receptor Melanocortin 5 receptor biology Chemistry Receptors Melanocortin digestive oral and skin physiology Melanocortin 4 receptor 030104 developmental biology HEK293 Cells Biochemistry Amino Acid Substitution biology.protein Molecular Medicine Agouti Signaling Protein Receptor Melanocortin Type 4 Melanocortin Energy Metabolism 030217 neurology & neurosurgery hormones hormone substitutes and hormone antagonists |
| Popis: | The melanocortin system consists of five reported receptors, agonists from the proopiomelanocortin gene transcript, and two antagonists, agouti-signaling protein (ASP) and agouti-related protein (AGRP). For both ASP and AGRP, the hypothesized Arg-Phe-Phe pharmacophores are on exposed β-hairpin loops. In this study, the Asn and Ala positions of a reported AGRP macrocyclic scaffold (c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro]) were explored with 14-compound and 8-compound libraries, respectively, to generate more potent, selective melanocortin receptor antagonists. Substituting diaminopropionic acid (Dap), DDap, and His at the Asn position yielded potent MC4R ligands, while replacing Ala with Ser maintained MC4R potency. Since these substitutions correlate to ASP loop residues, an additional Phe to Ala substitution was synthesized and observed to maintain MC4R potency. Seventeen compounds also possessed inverse agonist activity at the MC5R, the first report of this pharmacology. These findings are useful in developing molecular probes to study negative energy balance conditions and unidentified functions of the MC5R. |
| Databáze: | OpenAIRE |
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