小柯机器人

中国科学院分子细胞卓越创新中心汪胜和上海科技大学Jianjun Cheng研究组合作取得一项新突破。他们基于结构进行的新型第三代抗精神疾病药物(TGA)设计具有潜在的抗抑郁特性。这一研究成果于2021年12月9日发表在国际学术期刊《自然-神经科学》上。

在本研究中，研究人员解析了阿立哌唑和卡利拉嗪与5-HT2AR结合的晶体结构。两种TGA在5-HT2AR结合口袋中都采用了独特的“倒置”结构，二级药效团以类似于“螺栓”的方式插入。这种对TGA结合模式的深入了解提供了一种结构机制，这是它们在5-HT2AR和DRD2发挥不同部分功效的基础。

依托这些结构能够设计出DRD2/3和5-HT1AR的部分激动剂，其5-HT2AR结合可忽略不计，在小鼠中显示出有效的抗精神病样活性，而没有运动副作用。这种TGA还具有抗抑郁样作用，并通过5-HT1AR改善小鼠模型的认知能力。这项工作表明 5-HT2AR亲和力对于TGA治疗并无作用。

研究人员表示，多巴胺D2受体(DRD2)的部分激动剂活力是第三代抗精神病药的一个关键靶点。然而，TGA也可作为5-羟色胺（5-羟色胺；5-HT）2A受体（5-HT2AR）的拮抗剂或部分弱激动剂。

附：英文原文

Title: Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties

Author: Chen, Zhangcheng, Fan, Luyu, Wang, Huan, Yu, Jing, Lu, Dengyu, Qi, Jianzhong, Nie, Fen, Luo, Zhipu, Liu, Zhen, Cheng, Jianjun, Wang, Sheng

Issue&Volume: 2021-12-09

Abstract: Partial agonist activity at the dopamine D2 receptor (DRD2) is a key feature of third-generation antipsychotics (TGAs). However, TGAs also act as antagonists or weak partial agonists to the serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR). Here we present the crystal structures of aripiprazole- and cariprazine-bound human 5-HT2AR. Both TGAs adopt an unexpected ‘upside-down’ pose in the 5-HT2AR binding pocket, with secondary pharmacophores inserted in a similar way to a ‘bolt’. This insight into the binding modes of TGAs offered a structural mechanism underlying their varied partial efficacies at 5-HT2AR and DRD2. These structures enabled the design of a partial agonist at DRD2/3 and 5-HT1AR with negligible 5-HT2AR binding that displayed potent antipsychotic-like activity without motor side effects in mice. This TGA lead also had antidepressant-like effects and improved cognitive performance in mouse models via 5-HT1AR. This work indicates that 5-HT2AR affinity is a dispensable contributor to the therapeutic actions of TGAs.

DOI: 10.1038/s41593-021-00971-w

Source: https://www.nature.com/articles/s41593-021-00971-w

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex