Lan Yu, Chen Yin, Xu Xiangqing, Qiu Yinli, Liu Shicheng, Liu Xin, Liu Bi-Feng, Zhang Guisen
Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Jiangsu Nhwa Pharmaceutical Co., Ltd. 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
Eur J Med Chem. 2014 May 22;79:216-30. doi: 10.1016/j.ejmech.2014.04.019. Epub 2014 Apr 8.
The synthesis and sigma-1 receptor (σ1R) antagonist activity of a new series of 3,4-dihydro-2(1H)-quinolinone derivatives are reported. The new compounds were evaluated in vitro in sigma-1 and sigma-2 receptor-binding assays in guinea pig brain membranes. The structure-activity relationship led us to the promising derivative 7-(3-(piperidin-1-yl)propoxy)-1-(4-fluorobenzyl)-3,4-dihydro-2(1H)-quinolinone (35). The compounds with highest affinity and greatest selectivity were further profiled, and compound 35 had a high binding constant for sigma-1 receptor (Kiσ1 = 1.22 nM) and high sigma-1/2 selectivity (1066-fold). Thus, compound 35, which proved to be an antagonist of sigma-1 receptor, emerged as the most interesting candidate. In addition, compound 35 exerted dose-dependent anti-nociceptive effects in the formalin test. These characteristics suggested that the potent and selective compound 35 could be a potent candidate for pain treatment.
报道了一系列新型3,4-二氢-2(1H)-喹啉酮衍生物的合成及其σ1受体（σ1R）拮抗活性。在豚鼠脑膜的σ1和σ2受体结合试验中对新化合物进行了体外评估。构效关系使我们得到了有前景的衍生物7-(3-(哌啶-1-基)丙氧基)-1-(4-氟苄基)-3,4-二氢-2(1H)-喹啉酮（35）。对具有最高亲和力和最大选择性的化合物进行了进一步分析，化合物35对σ1受体具有高结合常数（Kiσ1 = 1.22 nM）和高σ1/σ2选择性（1066倍）。因此，被证明是σ1受体拮抗剂的化合物35成为了最有吸引力的候选物。此外，化合物35在福尔马林试验中表现出剂量依赖性的抗伤害感受作用。这些特性表明，强效且选择性的化合物35可能是疼痛治疗的有力候选药物。
