Structure鈥揂ctivity Relationships of Peptides Incorporating a Bioactive Reverse-Turn Heterocycle at the Melanocortin Receptors: Identification of a 5800-fold Mouse Melanocortin-3 Receptor (mMC3R) Selec

详细信息    查看全文

• 作者：Anamika Singh ; Marvin Dirain ; Rachel Witek ; James R. Rocca ; Arthur S. Edison ; Carrie Haskell-Luevano
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：56
• 期：7
• 页码：2747-2763
• 全文大小：963K
• 年卷期：v.56,no.7(April 11, 2013)
• ISSN：1520-4804

文摘

The melanocortin-3 (MC3) and melanocortin-4 (MC4) receptors regulate energy homeostasis, food intake, and associated physiological conditions. The melanocortin-4 receptor (MC4R) has been studied extensively. Less is known about specific physiological roles of the melanocortin-3 receptor (MC3R). A major obstacle to this lack of knowledge is attributed to a limited number of identified MC3R selective ligands. We previously reported a spatial scanning approach of a 10-membered thioether-heterocycle ring incorporated into a chimeric peptide template that identified a lead nM MC4R ligand. Upon the basis of those results, 17 compounds were designed and synthesized that focused upon modification in the pharmacophore domain. Notable results include the identification of a 0.13 nM potent 5800-fold mMC3R selective antagonist/slight partial agonist versus a 760 nM mMC4R full agonist (ligand 11). Biophysical experiments (two-dimensional ¹H NMR and computer-assisted molecular modeling) of this ligand resulted in the identification of an inverse 纬-turn secondary structure in the ligand pharmacophore domain.