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The extrapyramidal side effects of schizophrenia treatment can be significantly reduced by simultaneously targeting dopamine D 2 and serotonin 5-HT 2A receptors. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) models of D 2 receptor (CoMFA-1, q 2 = 0.767, r 2 = 0.969; CoMSIA-1, q 2 = 0.717, r 2 = 0.978) and 5-HT 2A receptor antagonists (CoMFA-2, q 2 = 0.703, r 2 = 0.946; CoMSIA-2, q 2 = 0.675, r 2 = 0.916) were successfully constructed using 35 tetrahydropyridopyrimidinone derivatives. Topomer CoMFA and HQSAR models were then constructed to further validate and supplement above models. Results showed that all models had good predictive power and stability. Contour map analysis revealed that the electrostatic and hydrophobic fields played vital roles in the bioactivity of dual antagonists. Molecular docking and molecular dynamic studies also suggested that the hydrogen bonding, electrostatic and hydrophobic interactions played key roles in the formation of stable binding sites. Meanwhile, several key residues like ASP114, TRP100, PHE389 of dopamine D 2 receptor and ASP134, PHE328, TRP324 of serotonin 5-HT 2A receptor were identified. Based on above findings, seven compounds were obtained through bioisostere replacement and ten compounds were designed by contour map analysis, in which the predicted activity of compounds S6 and DS2 were equivalent to that of the template compound 15 . 3D-QSAR and ADMET predictions indicated that all newly designed compounds had great biological activity and physicochemical properties. Moreover, based on the best pharmacophore model, four compounds ( Z1 , Z2 , Z3 and Z4 ) with new backbones were obtained by virtual screening. Overall, this study could provide theoretical guidance for the structural optimization, design and synthesis of novel dopamine D 2 and serotonin 5-HT 2A receptors dual antagonists. Abbreviations3D-QSARThree-dimensional quantitative structure-activity relationship5-HT 2A RSerotonin 5-hydroxytryptamine 5-HT 2A receptor5-HT 2C RSerotonin 5-hydroxytryptamine 5-HT 2C receptor receptorCADDComputer-aided drug designCoMFAComparative molecular field analysisCoMSIAComparative molecular similarity index analysisD 2 RDopamine D(2) receptorGPCRG-protein coupled receptorPLSPartial least squares regressionHQSARHologram quantitative structure-activity relationship. Communicated by Ramaswamy H. Sarma.

Herein we describe the hybridization of a benzoxazinone M1 scaffold with D2 privileged structures derived from putative and clinically relevant antipsychotics to develop designed multiple ligands. The M1 mAChR is an attractive target for the cognitive deficits in key CNS disorders. Moreover, activity at D2 and 5-HT2A receptors has proven useful for antipsychotic efficacy. We identified 9 which retained functional activity at the target M1 mAChR and D2R and demonstrated high affinity for the 5-HT2AR.