Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D1, D2 and serotonin 5-HT1A multi-action profile
Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D1, D2 and serotonin 5-HT1A multi-action profile
复制标题
DOI：
10.1016/j.bmc.2012.12.016
复制
发表时间：
2013-02-15
影响因子：
3.5
通讯作者：
Liu, Hong
中科院分区：
文献类型：
--
作者：
Sun, Haifeng;Zhu, Liyuan;Liu, Hong
建立了一种高效、快速的微波辅助合成L千金藤碱(L SPD)等四氢原黄连素(THPBs)关键中间体的制备方法。合成了31个A、D环不同取代基的THPB衍生物，并测定了它们与多巴胺D-1、D-2以及5-羟色胺5-羟色胺1A和5-羟色胺2A受体的亲和力。化合物18K和18M是D-1受体的部分激动剂，其K-I分别为50和6.3 nM，但均为D-2受体拮抗剂(K-I分别为305和145 nM)和5-HT1A受体完全激动剂(K-I分别为149和908 nM)。这两种THPBs化合物在动物模型中具有抗精神病作用。进一步的电生理学研究表明，18K兴奋的多巴胺(DA)能神经元与其5-HT1a受体激动剂活性有关。这些结果表明，这两个化合物针对多个神经递质受体，可能会为治疗精神分裂症提供具有新药理基础的新先导药物。(C)2012爱思唯尔有限公司。保留所有权利。
An effective and rapid method for the microwave-assisted preparation of the key intermediate for the total synthesis of tetrahydroprotoberberines (THPBs) including l-stepholidine (l-SPD) was developed. Thirty-one THPB derivatives with diverse substituents on A and D ring were synthesized, and their binding affinity to dopamine D-1, D-2 and serotonin 5-HT1A and 5-HT2A receptors were determined. Compounds 18k and 18m were identified as partial agonists at the D-1 receptor with K-i values of 50 and 6.3 nM, while both compounds act as D-2 receptor antagonists (K-i = 305 and 145 nM, respectively) and 5-HT1A receptor full agonists (K-i = 149 and 908 nM, respectively). These two THPBs compounds exerted antipsychotic actions in animal models. Further electrophysiological studies employing single-unit recording in intact animals demonstrated that 18k-excited dopaminergic (DA) neurons are associated with its 5-HT1A receptor agonistic activity. These results suggest that these two compounds targeted to multiple neurotransmitter receptors may present novel lead drugs with new pharmacological profiles for the treatment of schizophrenia. (C) 2012 Elsevier Ltd. All rights reserved.