Schizophrenia is a mental illness of not adequately understood causes that is not satisfactorily enough treated by current antipsychotics. In search for novel potential antipsychotics we performed structure-based virtual screening aimed to identify new dopamine D₂ receptor antagonists. We found compound D2AAK3 with affinity to dopamine D₂ receptor of 115 nM. D2AAK3 possesses additional nanomolar or low micromolar affinity to D₁, D₃, 5-HT_1A, 5-HT_2A and 5-HT₇ receptors, which makes it a good hit for further development as a multifunctional ligand. The compound has also some affinity to M₁ and H₁ receptors. We used homology modeling, molecular docking and molecular dynamics to study interactions of D2AAK3 with its molecular targets at the molecular level. In behavioral studies D2AAK3 decreases amphetamine-induced hyperactivity (when compared to the amphetamine-treated group) measured as spontaneous locomotor activity in mice. In addition, passive avoidance test demonstrated that D2AAK3 improves memory consolidation after acute treatment in mice. Elevated plus maze tests indicated that D2AAK3 induces anxiogenic activity 30 min after acute treatment, whereas this effect has no longer been observed 60 min after administration of the studied compound in mice.

精神分裂症是一种病因尚未充分了解的精神疾病，目前的抗精神病药物治疗效果不佳。为了寻找新的潜在抗精神病药，我们进行了基于结构的虚拟筛选，旨在鉴定新的多巴胺 D ₂受体拮抗剂。我们发现化合物 D2AAK3 对多巴胺 D ₂受体的亲和力为115 nM。D2AAK3 对 D ₁、D ₃、5-HT _1A、5-HT _2A和 5-HT ₇受体具有额外的纳摩尔或低微摩尔亲和力，这使其成为进一步开发作为多功能配体的良好选择。该化合物对 M ₁和 H ₁也有一定的亲和力受体。我们使用同源建模、分子对接和分子动力学在分子水平上研究 D2AAK3 与其分子靶标的相互作用。在行为研究中，D2AAK3 降低了苯丙胺诱导的多动症（与苯丙胺治疗组相比），测量为小鼠的自发运动活动。此外，被动回避测试表明，D2AAK3 可改善小鼠急性治疗后的记忆巩固。高架十字迷宫试验表明，D2AAK3 在急性治疗后 30 分钟诱导焦虑活性，而在小鼠中施用所研究的化合物 60 分钟后不再观察到这种作用。