Weichert Dietmar, Banerjee Ashutosh, Hiller Christine, Kling Ralf C, Hübner Harald, Gmeiner Peter
Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
J Med Chem. 2015 Mar 26;58(6):2703-17. doi: 10.1021/jm501889t. Epub 2015 Mar 12.
The development of biased (functionally selective) ligands provides a formidable challenge in medicinal chemistry. In an effort to learn to design functionally selective molecular tools for the highly therapeutically relevant dopamine D2 receptor, we synthesized a collection of agonists based on structurally distinct head groups derived from canonical or atypical dopaminergic pharmacophores. The test compounds feature a long lipophilic appendage that was shown to mediate biased signaling. By employing functional assays and molecular dynamics simulations, we could show that atypical dopamine surrogates of type 1 and 2 promote biased signaling, while ligands built from classical dopaminergic head groups (type 3 and 4) typically elicit more balanced signaling profiles. Besides this, we found a strong influence of the stereochemistry of type 4 aminotetraline-derived agonists on functional selectivity at D2 receptors. Whereas the (S)-enantiomer behaved as a full agonist, the biased ligand (R)-4 induced poor G protein coupling but substantial β-arrestin recruitment.
偏向性（功能选择性）配体的开发在药物化学中是一项艰巨的挑战。为了学会设计针对具有高度治疗相关性的多巴胺D2受体的功能选择性分子工具，我们基于源自经典或非典型多巴胺能药效基团的结构不同的头部基团合成了一系列激动剂。测试化合物具有一个长的亲脂性附属物，该附属物被证明可介导偏向性信号传导。通过采用功能测定和分子动力学模拟，我们可以表明1型和2型非典型多巴胺替代物可促进偏向性信号传导，而由经典多巴胺能头部基团构建的配体（3型和4型）通常会引发更平衡的信号传导谱。除此之外，我们发现4型氨基四氢萘衍生的激动剂的立体化学对D2受体的功能选择性有很大影响。(S)-对映体表现为完全激动剂，而偏向性配体(R)-4诱导不良的G蛋白偶联但大量的β- arrestin募集。
