Chen Xinyu, Klöckner Jessika, Holze Janine, Zimmermann Cornelia, Seemann Wiebke K, Schrage Ramona, Bock Andreas, Mohr Klaus, Tränkle Christian, Holzgrabe Ulrike, Decker Michael
Institute of Pharmacy and Food Chemistry, University of Würzburg , Am Hubland, 97074 Würzburg, Germany.
J Med Chem. 2015 Jan 22;58(2):560-76. doi: 10.1021/jm500860w. Epub 2014 Dec 19.
Aiming to design partial agonists for a G-protein-coupled receptor based on dynamic ligand binding, we synthesized three different series of bipharmacophoric ligands composed of the orthosteric building blocks iperoxo and 1 linked to allosteric modulators (BQCA-derived compounds, BQCAd; TBPB-derived compound, TBPBd). Their interactions were studied with the human muscarinic acetylcholine M1-receptor (hM1) with respect to receptor binding and Gq-protein signaling. Results demonstrate that iperoxo/BQCAd (2, 3) and 1/BQCAd hybrids (4) act as M1 partial agonists, whereas 1/TBPBd hybrids (5) did not activate M1-receptors. Among the iperoxo/BQCAd-hybrids, spacer length in conjunction with the pattern of substitution tuned efficacy. Most interestingly, a model of dynamic ligand binding revealed that the spacer length of 2a and 3a controlled the probability of switch between the inactive purely allosteric and the active bitopic orthosteric/allosteric binding pose. In summary, dynamic ligand binding can be exploited in M1 receptors to design partial agonists with graded efficacy.
为了基于动态配体结合设计G蛋白偶联受体的部分激动剂，我们合成了由正构结构单元iperoxo和与变构调节剂相连的1组成的三种不同系列的双药效团配体（BQCA衍生化合物，BQCAd；TBPB衍生化合物，TBPBd）。研究了它们与人毒蕈碱型乙酰胆碱M1受体（hM1）在受体结合和Gq蛋白信号传导方面的相互作用。结果表明，iperoxo/BQCAd（2,3）和1/BQCAd杂合物（4）作为M1部分激动剂，而1/TBPBd杂合物（5）未激活M1受体。在iperoxo/BQCAd杂合物中，间隔长度与取代模式共同调节药效。最有趣的是，动态配体结合模型表明，2a和3a的间隔长度控制了在无活性的纯变构和活性的双位点正构/变构结合构象之间切换的概率。总之，动态配体结合可用于M1受体，以设计具有分级药效的部分激动剂。
