Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D₁, D₂ and serotonin 5-HT_1A multi-action profile

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• 作者：Haifeng Sun^a ; ^&dagger ; ; Liyuan Zhu^b ; ^&dagger ; ; Huicui Yang^c ; Wangke Qian^a ; Lin Guo^b ; Shengbin Zhou^a ; Bo Gao^c ; Zeng Li^a ; Yu Zhou^a ; Hualiang Jiang^a ; Kaixian Chen^a ; Xuechu Zhen^b ; ^c ; ^{zhenxuechu@suda.edu.cn} ; Hong Liu^a ; ^{hliu@mail.shcnc.ac.cn}
• 关键词：Asymmetric synthesis ; Tetrahydroprotoberberines ; Dopamine receptors ; Serotonin receptors ; Multi-action ; New pharmacological profile
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：15 February, 2013
• 年：2013
• 卷：21
• 期：4
• 页码：856-868
• 全文大小：978 K

文摘

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 D₁, D₂ and serotonin 5-HT_1A and 5-HT_2A receptors were determined. Compounds rong class=""boldFont"">18krong> and rong class=""boldFont"">18mrong> were identified as partial agonists at the D₁ receptor with K_i values of 50 and 6.3 nM, while both compounds act as D₂ receptor antagonists (K_i = 305 and 145 nM, respectively) and 5-HT_1A 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 rong class=""boldFont"">18krong>-excited dopaminergic (DA) neurons are associated with its 5-HT_1A 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.