Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagiro, Buk-gu, 61005, South Korea.
Materials and Process Simulation Center (MC-139-74), California Institute of Technology, Pasadena, California, 91125, USA.
ChemMedChem. 2019 Oct 17;14(20):1783-1794. doi: 10.1002/cmdc.201900418. Epub 2019 Sep 26.
G -protein-biased agonists with minimal β-arrestin recruitment represent opportunities to overcome the serious adverse effects of human mu opioid receptor (μ-OR) agonists and developing alternative and safe treatments for pain. In order to discover novel non-morphinan opioid receptor agonists, we applied hierarchical virtual screening of our in-house database against a pharmacophore based on modeling the active conformations of opioid receptors. We discovered an initial hit compound, a novel μ-OR agonist with a pyrazoloisoquinoline scaffold. We applied computational R-group screening to this compound and synthesized 14 derivatives predicted to be the best. Of these, a new G -protein-biased compound, 1-{5-(3-chlorophenyl)-7,8-dimethoxy-3-[4-(methylsulfonyl)benzyl]-3H-pyrazolo[3,4-c]isoquinolin-1-yl}-N,N-dimethylmethanamine, showed an EC value of 179 nm against the μ-OR. This resulted in significant pain relief for mice in the phase II period of formalin response tests. This study provides a new strategy to identify diverse sets of promising compounds that might prove useful for the development of drugs that target other G-protein-coupled receptors.
G 蛋白偏向性激动剂与最小的β-arrestin 募集代表了克服人类μ阿片受体（μ-OR）激动剂的严重不良反应并开发用于疼痛的替代和安全治疗的机会。为了发现新型非吗啡阿片受体激动剂，我们应用了基于我们内部数据库的基于药效团的分层虚拟筛选，以模拟阿片受体的活性构象。我们发现了一种初始命中化合物，一种具有吡唑并异喹啉骨架的新型μ-OR 激动剂。我们对该化合物进行了计算 R 基团筛选，并合成了预测为最佳的 14 种衍生物。其中，一种新的 G 蛋白偏向性化合物，1-{5-（3-氯苯基）-7,8-二甲氧基-3-[4-（甲基磺酰基）苄基]-3H-吡唑并[3,4-c]异喹啉-1-基}-N,N-二甲基甲胺，对 μ-OR 的 EC 值为 179nm。这导致在福尔马林反应测试的第二阶段，小鼠的疼痛明显缓解。这项研究提供了一种新的策略来识别多样化的有前途的化合物，这些化合物可能有助于开发针对其他 G 蛋白偶联受体的药物。
