Convergent QSAR studies on a series of NK₃ receptor antagonists for schizophrenia treatment

Abstract

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 (q²= 0.810 and r²= 0.929) and acceptable HQSAR and CoMSIA models (HQSAR q²= 0.644 and r²= 0.910; CoMSIA q²= 0.691, r²= 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.

• CoMFA
• CoMSIA
• HQSAR
• NK₃ receptor antagonists
• schizophrenia

Acknowledgements

The authors thank NAP – Univ São Paulo Center for Innovation in Diagnostics & Therapeutics (IDx&T). We also thank OpenEye Scientific Software Inc. for providing Academic License of the software (ROCs and OMEGA 2). We thank alNAP – Univ São Paulo Center for Innovation in Diagnostics & Therapeutics (IDx&T). The authors also acknowledge Prof. Dr. Marcelo S. Castilho (Federal University of Bahia/Brazil) for having provided access to Pirouette 3.11 software.

Declaration of interest

The authors would like to thank FAPESP (M. C. P. 2013/15947-3), CAPES, and CNPq (G. H. G. T. 477002/2013-7) for financial funding.

Supplementary material available online Supplementary Figures 1-3 and Tables 1-6.