Differential profile of typical, atypical and third generation antipsychotics at human 5-HT7a receptors coupled to adenylyl cyclase: detection of agonist and inverse agonist properties
Differential profile of typical, atypical and third generation antipsychotics at human 5-HT7a receptors coupled to adenylyl cyclase: detection of agonist and inverse agonist properties
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DOI：
10.1007/s00210-007-0182-6
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发表时间：
2007-10-01
影响因子：
3.6
通讯作者：
Cussac, Didier
中科院分区：
文献类型：
--
作者：
Rauly-Lestienne, Isabelle;Boutet-Robinet, Elisa;Cussac, Didier
5-HT7受体存在于丘脑和边缘结构中，这些受体在精神分裂症病理中的可能作用已被唤起。在这项研究中，我们检测了一系列抗精神病药物在这些受体上的结合亲和力和激动剂/拮抗剂/逆激动剂特性，即优先靶向D-2和5-HT1A位点的典型、非典型和第三代化合物。在稳定表达人(h) 5-HT7a受体亚型的HEK293细胞中测定腺苷酸环化酶（AC）活性。5-HT和5-CT使环腺苷单磷酸水平提高了约20倍，而(+)-8-OH-DPAT、抗运动障碍剂沙唑坦和新型抗精神病药物苯丙诺在h5-HT7a受体刺激AC时表现出部分激动剂特性。其他化合物拮抗5-HT诱导的AC活性，其pK(B)值与pK(i)相关，这是通过与[H-3] 5-CT的竞争结合确定的。选择性5-HT7受体配体SB269970是最有效的拮抗剂。抗精神病药物的拮抗效价（pK(B)）依次为齐拉西酮>硫螺酮> SSR181507 >=氯氮平>=奥氮平> SLV-314 > SLV-313 >=阿立哌唑>=氯丙嗪>奈莫那匹利>氟哌啶醇。有趣的是，用forskolin预处理HEK293-h5-HT7a细胞增强了基础AC活性，并显示出对典型和非典型抗精神病药物以及阿立哌唑的逆激动剂特性。相比之下，其他新型抗精神病药物表现出不同的5-HT7a性质；如上所述，SLV-313和SLV-314作为准中性拮抗剂，SSR181507作为逆激动剂，而苯丙腈作为部分激动剂。综上所述，第三代抗精神病药物在5-HT7受体上的不同特性可能会影响它们的抗精神病作用。
5-HT7 receptors are present in thalamus and limbic structures, and a possible role of these receptors in the pathology of schizophrenia has been evoked. In this study, we examined binding affinity and agonist/antagonist/inverse agonist properties at these receptors of a large series of antipsychotics, i.e., typical, atypical, and third generation compounds preferentially targeting D-2 and 5-HT1A sites. Adenylyl cyclase (AC) activity was measured in HEK293 cells stably expressing the human (h) 5-HT7a receptor isoform. 5-HT and 5-CT increased cyclic adenosine monophosphate level by about 20-fold whereas (+)-8-OH-DPAT, the antidyskinetic agent sarizotan, and the novel antipsychotic compound bifeprunox exhibited partial agonist properties at h5-HT7a receptors stimulating AC. Other compounds antagonized 5-HT-induced AC activity with pK(B) values which correlated with their pK(i) as determined by competition binding vs [H-3] 5-CT. The selective 5-HT7 receptor ligand, SB269970, was the most potent antagonist. For antipsychotic compounds, the following rank order of antagonism potency (pK(B)) was ziprasidone > tiospirone > SSR181507 >= clozapine >= olanzapine > SLV-314 > SLV-313 >= aripiprazole >= chlorpromazine > nemonapride > haloperidol. Interestingly, pretreatment of HEK293-h5-HT7a cells with forskolin enhanced basal AC activity and revealed inverse agonist properties for both typical and atypical antipsychotics as well as for aripiprazole. In contrast, other novel antipsychotics exhibited diverse 5-HT7a properties; SLV-313 and SLV-314 behaved as quasi-neutral antagonists, SSR181507 acted as an inverse agonist, and bifeprunox as a partial agonist, as mentioned above. In conclusion, the differential properties of third generation antipsychotics at 5-HT7 receptors may influence their antipsychotic profile.