Primi Marina Candido, Maltarollo Vinícius Gonçalves, Magalhães Juliana Gallottini, de Sá Matheus Malta, Rangel-Yagui Carlota Oliveira, Trossini Gustavo Henrique Goulart
a Department of Pharmacy, Faculty of Pharmaceutical Sciences , University of São Paulo , SP , Brazil .
b Laboratory of Genetics and Molecular Cardiology , Heart Institute (InCor), University of São Paulo Medical School , SP , Brazil , and.
J Enzyme Inhib Med Chem. 2016;31(2):283-94. doi: 10.3109/14756366.2015.1021250. Epub 2015 Apr 9.
The dopamine hypothesis states that decreased dopaminergic neurotransmission reduces schizophrenia symptoms. Neurokinin-3 receptor (NK3) antagonists reduce dopamine release and have shown positive effects in pre-clinical and clinical trials. We employed 2D and 3D-QSAR analysis on a series of 40 non-peptide NK3 antagonists. Multivariate statistical analysis, PCA and HCA, were performed to rational training/test set splitting and PLS regression was employed to construct all QSAR models. We constructed one highly predictive CoMFA model (q(2)= 0.810 and r(2)= 0.929) and acceptable HQSAR and CoMSIA models (HQSAR q(2)= 0.644 and r(2)= 0.910; CoMSIA q(2)= 0.691, r(2)= 0.911). The three different techniques provided convergent physicochemical results. All models indicate cyclopropane, piperidine and di-chloro-phenyl ring attached to cyclopropane ring and also the amide group attached to the piperidine ring could play an important role in ligand-receptor interactions. These findings may contribute to develop potential NK3 receptor antagonists for schizophrenia.
多巴胺假说认为，多巴胺能神经传递减少可减轻精神分裂症症状。神经激肽-3受体（NK3）拮抗剂可减少多巴胺释放，并已在临床前和临床试验中显示出积极效果。我们对一系列40种非肽类NK3拮抗剂进行了二维和三维定量构效关系（QSAR）分析。进行了多变量统计分析、主成分分析（PCA）和层次聚类分析（HCA）以合理划分训练集/测试集，并采用偏最小二乘回归（PLS）构建所有QSAR模型。我们构建了一个预测性很高的比较分子场分析（CoMFA）模型（交叉验证系数q(2)=0.810，决定系数r(2)=0.929）以及可接受的全息定量构效关系（HQSAR）和比较分子相似性指数分析（CoMSIA）模型（HQSAR的q(2)=0.644，r(2)=0.910；CoMSIA的q(2)=0.691，r(2)=0.911）。这三种不同技术提供了趋同的物理化学结果。所有模型均表明，环丙烷、哌啶以及连接在环丙烷环上的二氯苯环，还有连接在哌啶环上的酰胺基团在配体-受体相互作用中可能发挥重要作用。这些发现可能有助于开发用于治疗精神分裂症的潜在NK3受体拮抗剂。
