Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215123, China.
Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University , Suzhou, Jiangsu 215123, China.
J Chem Inf Model. 2017 Jun 26;57(6):1474-1487. doi: 10.1021/acs.jcim.7b00188. Epub 2017 May 15.
Among non-dopaminergic strategies for combating Parkinson's disease (PD), antagonism of the A adenosine receptor (AR) has emerged to show great potential. In this study, on the basis of two crystal structures of the A AR with the best capability to distinguish known antagonists from decoys, docking-based virtual screening (VS) was conducted to identify novel A AR antagonists. A total of 63 structurally diverse compounds identified by VS were submitted to experimental testing, and 11 of them exhibited substantial activity against the A AR (K < 10 μM), including two compounds with K below 1 μM (compound 43, 0.42 μM; compound 51, 0.27 μM) and good A/A selectivity (fold < 0.1). Compounds 43 and 51 demonstrated antagonistic activity according to the results of cAMP measurements (cAMP IC = 1.67 and 1.80 μM, respectively) and showed good efficacy in the haloperidol-induced catalepsy (HIC) rat model for PD at doses of up to 30 mg/kg. Further lead optimization based on a substructure searching strategy led to the discovery of compound 84 as an excellent A AR antagonist (A K = 54 nM, A/A fold < 0.1, cAMP IC = 0.3 μM) that exhibited significant improvement in anti-PD efficacy in the HIC rat model.
在治疗帕金森病（PD）的非多巴胺能策略中，A 腺苷受体（AR）拮抗剂显示出巨大的潜力。在这项研究中，基于能够最好地区分已知拮抗剂和诱饵的两种 A AR 晶体结构，进行了基于对接的虚拟筛选（VS），以鉴定新型 A AR 拮抗剂。通过 VS 鉴定的 63 种结构多样的化合物被提交进行实验测试，其中 11 种对 A AR 具有显著活性（K < 10 μM），包括两种 K 值低于 1 μM 的化合物（化合物 43，0.42 μM；化合物 51，0.27 μM）和良好的 A/A 选择性（比值 < 0.1）。根据 cAMP 测量的结果（cAMP IC = 1.67 和 1.80 μM，分别），化合物 43 和 51 表现出拮抗活性，并在高达 30 mg/kg 的剂量下在用于 PD 的氟哌啶醇诱导的僵住症（HIC）大鼠模型中表现出良好的疗效。进一步基于亚结构搜索策略的先导优化导致发现化合物 84 作为一种优秀的 A AR 拮抗剂（A K = 54 nM，A/A 比值 < 0.1，cAMP IC = 0.3 μM），在 HIC 大鼠模型中显著提高了抗 PD 疗效。
