The intricate involvement of the serotonin 5-HT_2A receptor (5-HT_2AR) both in schizophrenia and in the activity of antipsychotic drugs is widely acknowledged. The currently marketed antipsychotic drugs, although effective in managing the symptoms of schizophrenia to a certain extent, are not without their repertoire of serious side effects. There is a need for better therapeutics to treat schizophrenia for which understanding the mechanism of action of the current antipsychotic drugs is imperative. With bioluminescence resonance energy transfer (BRET) assays, we trace the signaling signature of six antipsychotic drugs belonging to three generations at the 5-HT_2AR for the entire spectrum of signaling pathways activated by serotonin (5-HT). The antipsychotic drugs display previously unidentified pathway preference at the level of the individual Gα subunits and β-arrestins. In particular, risperidone, clozapine, olanzapine and haloperidol showed G protein-selective inverse agonist activity. In addition, G protein-selective partial agonism was found for aripiprazole and cariprazine. Pathway-specific apparent dissociation constants determined from functional analyses revealed distinct coupling-modulating capacities of the tested antipsychotics at the different 5-HT-activated pathways. Computational analyses of the pharmacological and structural fingerprints support a mechanistically based clustering that recapitulate the clinical classification (typical/first generation, atypical/second generation, third generation) of the antipsychotic drugs. The study provides a new framework to functionally classify antipsychotics that should represent a useful tool for the identification of better and safer neuropsychiatric drugs and allows formulating hypotheses on the links between specific signaling cascades and in the clinical outcomes of the existing drugs.

_{血清素 5-HT 2A}受体 (5-HT _2A R) 在精神分裂症和抗精神病药物活性中的复杂参与已得到广泛认可。目前市售的抗精神病药物虽然在一定程度上可以有效控制精神分裂症的症状，但并非没有严重的副作用。需要更好的治疗方法来治疗精神分裂症，为此了解当前抗精神病药物的作用机制势在必行。通过生物发光共振能量转移 (BRET) 测定，我们追踪了属于三代的六种抗精神病药物在 5-HT _2A R 处的信号特征，以了解由血清素 (5-HT) 激活的整个信号通路谱。抗精神病药物在单个 Gα 亚基和 β-arrestins 水平上表现出先前未识别的途径偏好。特别是，利培酮、氯氮平、奥氮平和氟哌啶醇表现出 G 蛋白选择性反向激动剂活性。此外，还发现阿立哌唑和卡利拉嗪具有 G 蛋白选择性部分激动作用。通过功能分析确定的途径特异性表观解离常数揭示了所测试的抗精神病药物在不同 5-HT 激活途径中的不同耦合调节能力。药理学和结构指纹的计算分析支持基于机械的聚类，概括了抗精神病药物的临床分类（典型/第一代、非典型/第二代、第三代）。该研究提供了一个对抗精神病药物进行功能分类的新框架，该框架应该成为识别更好、更安全的神经精神药物的有用工具，并允许对特定信号级联与现有药物临床结果之间的联系提出假设。