Mo Jiao, Guo Yang, Yang Yu-She, Shen Jing-Shan, Jin Guo-Zhang, Zhen Xuechu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Curr Med Chem. 2007;14(28):2996-3002. doi: 10.2174/092986707782794050.
Tetrahydroprotoberberines (THPBs) represent a series of compounds extracted from the Chinese herb Corydalis ambigua and various species of Stephania. THPBs, dependent on the presence of hydroxyl groups in its structure, are divided into three types: nonhydroxyl-THPBs, monohydroxyl-THPBs and dihydroxyl-THPBs. THPBs are identified as a new category of dopamine receptor ligands. Among all THPBs, dihydroxyl-THPBs attracted particular attention because of their dual actions on dopamine (DA) receptors. They exhibit D(1) receptor agonistic activity while acting as D(2) receptor antagonists. This unique pharmacological profile made dihydroxyl-THPBs such as l-stepholidine (l-SPD) potential agents in the treatment of drug addiction, Parkinson's disease, and especially, schizophrenia. Clinical studies have shown that co-administration of l-SPD with a typical antipsychotic drug significantly enhances the therapeutic effects and remarkably reduces the tardive dyskinesia induced by the typical antipsychotic drug used with schizophrenic patients. Moreover, l-SPD alone was shown to have therapeutic value without inducing significant extrapyramidal side effects and also seemed to reduce the negative symptoms of schizophrenia. This is confirmed in experimental studies using animal models of schizophrenia, in which l-SPD improved social interaction and cognitive function, inhibited hyperactivity in schizophrenic animals. This review discusses the chemistry, pharmacology and clinical implications of l-THPBs in the drug development for psychosis and neurobiological diseases.
四氢原小檗碱（THPBs）是从中药延胡索和多种千金藤属植物中提取的一系列化合物。根据其结构中羟基的存在情况，THPBs可分为三类：非羟基THPBs、单羟基THPBs和二羟基THPBs。THPBs被鉴定为一类新的多巴胺受体配体。在所有THPBs中，二羟基THPBs因其对多巴胺（DA）受体的双重作用而备受关注。它们在作为D(2)受体拮抗剂时表现出D(1)受体激动活性。这种独特的药理学特性使l-千金藤啶碱（l-SPD）等二羟基THPBs成为治疗药物成瘾、帕金森病，尤其是精神分裂症的潜在药物。临床研究表明, l-SPD与典型抗精神病药物联合使用可显著增强治疗效果，并显著降低精神分裂症患者使用典型抗精神病药物引起的迟发性运动障碍。此外，单独使用l-SPD也具有治疗价值，不会引起明显的锥体外系副作用，而且似乎还能减轻精神分裂症的阴性症状。这在使用精神分裂症动物模型的实验研究中得到了证实，其中l-SPD改善了社交互动和认知功能，抑制了精神分裂症动物的多动行为。本文综述了左旋四氢原小檗碱在精神病和神经生物学疾病药物开发中的化学、药理学及临床意义。
