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.
J Med Chem. 2018 Nov 21;61(22):10017-10039. doi: 10.1021/acs.jmedchem.8b01096. Epub 2018 Nov 9.
Herein, a novel series of multireceptor ligands was developed as polypharmacological antipsychotic agents using the designed multiple ligand approach between dopamine receptors and serotonin receptors. Among them, compound 47 possessed unique pharmacological features, exhibiting high affinities for D, D, 5-HT, 5-HT, and 5-HT receptors and low efficacy at the off-target receptors (5-HT, histamine H, and adrenergic α receptor). Compound 47 showed dose-dependent inhibition of apomorphine- and MK-801-induced motor behavior, and the conditioned avoidance response with low cataleptic effect. Moreover, compound 47 resulted nonsignificantly serum prolactin levels and weight gain change compared with risperidone. Additionally, compound 47 possessed a favorable pharmacokinetic profile with oral bioavailability of 58.8% in rats. Furthermore, compound 47 displayed procognition properties in a novel object recognition task in rats. Taken together, compound 47 may constitute a novel class of atypical antipsychotic drugs for schizophrenia.
本文开发了一系列新型多受体配体，作为多巴胺受体和 5-羟色胺受体之间的设计多配体方法的多药效抗精神病药物。其中，化合物 47 具有独特的药理学特征，对 D、D、5-HT、5-HT 和 5-HT 受体具有高亲和力，对非靶点受体（5-HT、组胺 H 和肾上腺素能α受体）的效能较低。化合物 47 表现出剂量依赖性抑制阿朴吗啡和 MK-801 诱导的运动行为，以及条件回避反应，且对类帕金森氏病作用较弱。此外，与利培酮相比，化合物 47 对血清催乳素水平和体重增加的影响无显著差异。此外，化合物 47 在大鼠体内具有良好的药代动力学特征，口服生物利用度为 58.8%。此外，化合物 47 在大鼠新物体识别任务中表现出认知特性。总之，化合物 47 可能构成一类新型的用于治疗精神分裂症的非典型抗精神病药物。
