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

Author(s)

Primi, Marina Candido ^[1] ; Maltarollo, Vinicius Goncalves ^[1] ; Magalhaes, Juliana Gallottini ^[1] ; de Sa, Matheus Malta ^[2] ; Rangel-Yagui, Carlota Oliveira ^[3] ; Goulart Trossini, Gustavo Henrique ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, BR-05508 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Sch Med, Heart Inst InCor, Lab Genet & Mol Cardiol, BR-05508 Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Biochem & Pharmaceut Technol, BR-05508 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Journal of Enzyme Inhibition and Medicinal Chemistry; v. 31, n. 2, p. 283-294, MAR 3 2016.
• Web of Science Citations: 2

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 (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. (AU)

• FAPESP's process: 13/15947-3 - New antituberculosis agents candidates: design and synthesis of phosphopantetheine adenylyltransferase inhibitors
• Grantee: Marina Candido Primi
• Support Opportunities: Scholarships in Brazil - Doctorate