Van der Poorten Olivier, Fehér Krisztina, Buysse Koen, Feytens Debby, Zoi Ioanna, Schwartz Steven D, Martins José C, Tourwé Dirk, Cai Minying, Hruby Victor J, Ballet Steven
Research Group of Organic Chemistry, Vrije Universiteit Brussel , Pleinlaan 2, B-1050 Brussels, Belgium.
Department of Organic Chemistry, University of Ghent , Krijgslaan 281 S4, 9000 Ghent, Belgium.
ACS Med Chem Lett. 2014 Dec 3;6(2):192-7. doi: 10.1021/ml500436s. eCollection 2015 Feb 12.
To address the need for highly potent, metabolically stable, and selective agonists, antagonists, and inverse agonists at the melanocortin receptor subtypes, conformationally constrained indolo- and benzazepinone residues were inserted into the α-MSH pharmacophore, His(6)-Phe(7)-Arg(8)-Trp(9)-domain. Replacement of His(6) by an aminoindoloazepinone (Aia) or aminobenzazepinone (Aba) moiety led to hMC4R and hMC5R selective agonist and antagonist ligands, respectively (tetrapeptides 1 to 3 and 4, respectively). In peptides 1 to 3 and depending on the para-substituent of the d-Phe residue in position 2, the activity goes from allosteric partial agonism (1, R = H) to allosteric full agonism (2, R = F) and finally allosteric partial agonism (3, R = Br).
为满足对黑皮质素受体亚型具有高效能、代谢稳定且具选择性的激动剂、拮抗剂及反向激动剂的需求，将构象受限的吲哚和苯并氮杂䓬酮残基插入α-MSH药效基团His(6)-Phe(7)-Arg(8)-Trp(9)结构域。用氨基吲哚氮杂䓬酮（Aia）或氨基苯并氮杂䓬酮（Aba）部分取代His(6)，分别得到了对人黑素皮质素4型受体（hMC4R）和人黑素皮质素5型受体（hMC5R）具有选择性的激动剂和拮抗剂配体（分别为四肽1至3和4）。在肽1至3中，根据第2位d-Phe残基的对位取代基不同，活性从变构部分激动作用（1，R = H）变为变构完全激动作用（2，R = F），最后又变为变构部分激动作用（3，R = Br）。
