RESUMO
The purpose of the present study aims to develop a satisfactory model for predicting pro-social and pro-cognitive effects on azinesulfonamides of cyclic amine derivatives as potential antipsychotics. The three dimensional-quantitative structure affinity relationship (3D-QSAR) study was performed on a series of azinesulfonamides of cyclic amine derivative using comparative molecular similarity indices analysis (CoMSIA). The best statistical model of CoMSIA q2, r2, SEE and F values are 0.664, 0.973, 0.087, and 82.344, respectively. Based on the model contour maps and the highest activity structure of the 43rd compound, serial new structures were designed and the 43k1 compound was selected as the best structure. The dock results showed a good binding of 43k1 with the protein (PDB ID: 6A93). The QSAR model analysis of the contour maps can help us to provide guidelines for finding novel potential antipsychotics.
Assuntos
Antipsicóticos , Transtorno Autístico , Humanos , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Chumbo , Antipsicóticos/farmacologia , AminasRESUMO
A series of azinesulfonamides of long-chain arylpiperazine derivatives with semi-rigid alkylene spacer was designed, synthesized, and biologically evaluated using in vitro methods for their affinity for dopaminergic D2 and serotoninergic 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7 receptors. Docking to homology models revealed a possible halogen bond formation in complexes of the most potent ligands and the target receptors. The study allowed for the identification of compound 5-({4-(2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl)piperidin-1-yl}sulfonyl)quinoline (21), which behaved as D2, 5-HT1A and 5-HT7 receptor antagonist. In preliminary in vivo studies, compound 21 displayed distinct antipsychotic properties in the MK-801-evoked hyperactivity test in mice at a dose of 10mg/kg, and exerted antidepressant-like effect in a forced swim test in mice (MED=0.625mg/kg, i.p.).
Assuntos
Antidepressivos/química , Antipsicóticos/química , Piperazinas/química , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Sulfonamidas/química , Animais , Antidepressivos/síntese química , Antidepressivos/farmacologia , Antipsicóticos/síntese química , Antipsicóticos/farmacologia , Sítios de Ligação , Maleato de Dizocilpina/farmacologia , Halogênios/química , Concentração Inibidora 50 , Ligantes , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Atividade Motora/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/farmacologia , Estrutura Terciária de Proteína , Receptor 5-HT1A de Serotonina/química , Receptores de Dopamina D2/química , Receptores de Serotonina/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologiaRESUMO
A series of azinesulfonamide derivatives of long-chain arylpiperazines with variable-length alkylene spacers between sulfonamide and 4-arylpiperazine moiety is designed, synthesized, and biologically evaluated. In vitro methods are used to determine their affinity for serotonin 5-HT1A, 5-HT6, 5-HT7, and dopamine D2 receptors. X-ray analysis, two-dimensional NMR conformational studies, and docking into the 5-HT1A and 5-HT7 receptor models are then conducted to investigate the conformational preferences of selected serotonin receptor ligands in different environments. The bent conformation of tetramethylene derivatives is found in a solid state, in dimethyl sulfoxide, and as a global energy minimum during conformational analysis in a simulated water environment. Furthermore, ligand geometry in top-scored complexes is also bent, with one torsion angle in the spacer (τ2) in synclinal conformation. Molecular docking studies indicate the role of halogen bonding in complexes of the most potent ligands and target receptors.