title: 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 (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.
authors: a Department of Pharmacy, Faculty of Pharmaceutical Sciences , University of São Paulo , SP , Brazil .
authors: Marina Candido
authors: MC
authors: Primi
authors: a Department of Pharmacy, Faculty of Pharmaceutical Sciences , University of São Paulo , SP , Brazil .
authors: Vinícius Gonçalves
authors: VG
authors: Maltarollo
authors: a Department of Pharmacy, Faculty of Pharmaceutical Sciences , University of São Paulo , SP , Brazil .
authors: Juliana Gallottini
authors: JG
authors: Magalhães
authors: b Laboratory of Genetics and Molecular Cardiology , Heart Institute (InCor), University of São Paulo Medical School , SP , Brazil , and.
authors: Matheus Malta
authors: MM
authors: de Sá
authors: c Department of Biochemical and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences , University of São Paulo , SP , Brazil.
authors: Carlota Oliveira
authors: CO
authors: Rangel-Yagui
authors: a Department of Pharmacy, Faculty of Pharmaceutical Sciences , University of São Paulo , SP , Brazil .
authors: Gustavo Henrique Goulart
authors: GH
authors: Trossini
mesh_terms: D003521:Cyclopropanes / Q000737:chemistry; D006801:Humans; D010880:Piperidines / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D012559:Schizophrenia / Q000188:drug therapy*
chemical_list: D003521:Cyclopropanes; D010880:Piperidines; D018042:Receptors, Neurokinin-3; C032727:piperidine; C030797:cyclopropane
keywords: CoMFA; CoMSIA; HQSAR; NK3 receptor antagonists; schizophrenia