Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland.
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
Biomolecules. 2020 Feb 24;10(2):349. doi: 10.3390/biom10020349.
-(2-hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1-benzimidazol -1-yl)propyl]piperidine-4-carboxamide (D2AAK4) is a multitarget ligand of aminergic G protein-coupled receptors (GPCRs) identified in structure-based virtual screening. Here we present detailed in vitro, in silico and in vivo investigations of this virtual hit. D2AAK4 has an atypical antipsychotic profile and low affinity to off-targets. It interacts with aminergic GPCRs, forming an electrostatic interaction between its protonatable nitrogen atom and the conserved Asp 3.32 of the receptors. At the dose of 100 mg/kg D2AAK4 decreases amphetamine-induced hyperactivity predictive of antipsychotic activity, improves memory consolidation in passive avoidance test and has anxiogenic properties in elevated plus maze test (EPM). Further optimization of the virtual hit D2AAK4 will be aimed to balance its multitarget profile and to obtain analogs with anxiolytic activity.
-(2-羟苯基)-1-[3-(2-氧代-2,3-二氢-1-苯并咪唑-1-基)丙基]哌啶-4-甲酰胺(D2AAK4)是一种基于结构的虚拟筛选中鉴定的多靶标胺能 G 蛋白偶联受体(GPCR)配体。在这里，我们对这一虚拟命中进行了详细的体外、计算和体内研究。D2AAK4 具有非典型抗精神病作用特征和低亲和力的非靶点。它与胺能 GPCR 相互作用，在其可质子化的氮原子和受体的保守的 Asp 3.32 之间形成静电相互作用。在 100mg/kg 的剂量下，D2AAK4 可降低安非他命诱导的多动性，预测具有抗精神病作用，改善被动回避测试中的记忆巩固，并在高架十字迷宫测试(EPM)中具有焦虑作用。对虚拟命中 D2AAK4 的进一步优化将旨在平衡其多靶标特征，并获得具有抗焦虑活性的类似物。
