Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa1-Arg-(pI)DPhe-Xaa4-NH2
| Autor: | Skye R. Doering, Radleigh G. Santos, Erica M. Haslach, Robert C. Speth, Jon R. Appel, Sathya M. Schnell, Phaedra Geer, Ginamarie Debevec, Katie T. Freeman, Clemencia Pinilla, Carrie Haskell-Luevano, Marvin L. Dirain, Richard A. Houghten, Marc A. Giulianotti |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Stereochemistry Pharmacology 01 natural sciences Article 03 medical and health sciences Mice Peptide Library Drug Discovery Pi Animals Amino Acid Sequence Receptor Oligopeptide Tetrapeptide 010405 organic chemistry Chemistry Drug discovery Antagonist 0104 chemical sciences Melanocortin 4 receptor 030104 developmental biology Molecular Medicine Receptor Melanocortin Type 4 Melanocortin Oligopeptides Receptor Melanocortin Type 3 |
| Popis: | The centrally expressed melanocortin-3 and -4 receptors (MC3R/MC4R) have been studied as possible targets for weight management therapies, with a preponderance of studies focusing on the MC4R. Herein, a novel tetrapeptide scaffold [Ac-Xaa1 -Arg-(pI)DPhe-Xaa4 -NH2] is reported. The scaffold was derived from results obtained from a MC3R mixture-based positional scanning campaign. From these results, a set of 48 tetrapeptides were designed and pharmacologically characterized at the mouse melanocortin-1, -3, -4, and -5 receptors. This resulted in the serendipitous discovery of nine compounds that were MC3R agonists (EC50 < 1,000 nM) and MC4R antagonists (5.7 |
| Databáze: | OpenAIRE |
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