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.
Keywords: CoMFA; CoMSIA; HQSAR; NK3 receptor antagonists; schizophrenia.