Geissoschizine methyl ether has third-generation antipsychotic-like actions at the dopamine and serotonin receptors
Geissoschizine methyl ether has third-generation antipsychotic-like actions at the dopamine and serotonin receptors
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DOI：
10.1016/j.ejphar.2011.09.007
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发表时间：
2011-12-05
影响因子：
5
通讯作者：
Shimada, Shoichi
中科院分区：
文献类型：
--
作者：
Ueda, Takashi;Ugawa, Shinya;Shimada, Shoichi
阿立哌唑对精神分裂症和相关疾病的治疗做出了重大贡献。它改善了其安全性和耐受性，这些作用归因于其对5-羟色胺和多巴胺D（2）受体的药理学作用。为了发现具有相似药理学特征的化合物，我们引入了一种通用的基于单细胞的钙成像测定，该测定对先前阿立哌唑研究中使用的各种测定的读数进行了分析。在本试验中，血清素5-HT（1A）、5-HT（2A）、5-HT（2C）、5-HT（7）和多巴胺D（2L）受体的已知配体的功效和效力与使用各种读数的先前研究中发现的那些相当。所开发的测定还能够再现阿立哌唑在多巴胺D（2L）受体上的部分激动剂活性、低内在活性和选择性激活。在相同的实验条件下，植物吲哚生物碱Geissoconavine Methyl ether（GM）对5-HT_（1A）受体表现为部分激动剂，对多巴胺D（2L）受体表现为部分激动/拮抗剂，对5-HT_（2A）、5-HT（2C）和5-HT_（7）受体表现为拮抗剂。有趣的是，GM表现出相对较低的内在活性，并在表达多巴胺D（2L）受体的细胞亚群中引起部分活化反应;阿立哌唑也观察到类似的这两种作用。尽管GM对多巴胺受体的作用远不如阿立哌唑对多巴胺D（2L）受体的作用（GM的EC（50）= 4.4 μ M，而阿立哌唑的EC（50）= 56 nM），但GM和GM衍生物可能构成一组新的非典型抗精神病药物候选药物。(C)2011 Elsevier B. V.保留所有权利。
Aripiprazole has made a significant contribution to the treatment of schizophrenia and related disorders. It has improved its safety and tolerability profiles, and these effects have been attributed to its pharmacological profile at the serotonin 5-HT and dopamine D(2) receptors. To discover compounds that have a similar pharmacological profile, we introduced a generic single-cell-based calcium imaging assay that standardizes the readouts from various assays used in previous studies on aripiprazole. In the present assay, the efficacy and potency of known ligands of serotonin 5-HT(1A), 5-HT(2A), 5-HT(2C), 5-HT(7) and dopamine D(2L) receptors were comparable to those found in previous studies using a variety of readouts. The developed assay was also able to reproduce the partial agonist activity, the low intrinsic activity and the selective activation of aripiprazole at the dopamine D(2L) receptors. Under identical experimental conditions, geissoschizine methyl ether (GM), a plant indole alkaloid, behaved as a partial agonist at the serotonin 5-HT1A receptor, a partial agonist/antagonist at the dopamine D(2L) receptor and an antagonist at the serotonin 5-HT2A, 5-HT(2C) and 5-HT7 receptors. Interestingly, GM showed a relatively low intrinsic activity and evoked a partial activation response in a subset of cells expressing the dopamine D(2L) receptor; both of these effects were similarly observed for aripiprazole. Although GM is far less potent at the dopamine receptor than aripiprazole at dopamine D(2L) receptors (EC(50) = 4.4 mu M for GM vs. EC(50) = 56 nM for aripiprazole), GM and GM derivatives may comprise a new set of candidates for atypical antipsychotics. (C) 2011 Elsevier B.V. All rights reserved.