(-),(+)黄皮酰胺对鼠脑内 NMDA- 受体的影响

用[³H]MK-801放射配体竟争结合法测定了(-),(+)黄皮酰胺对大鼠前脑,海马,皮层等部位突触膜的NMDA-R的作用,以探讨其促智机制。同时用饱和实验分析po给药10d后,小鼠脑内该受体密度的变化。结果表明:(-),(+)黄皮酰胺对脑内各部位的NMDA受体均无特异亲和力。但(-)黄皮酰胺在体给药10d后能使小鼠脑内NMDA受体密度显著增高,并呈一定的量效关系。提示黄皮酰胺的药理作用有光学选择性;(-)黄皮酰胺增加脑内NMDA受体密度为其促智作用提供了重要理论依据。     

(-),( )黄皮酰胺对樟柳碱引起的小鼠脑内乙酰胆碱含量降低及记忆障碍的影响

为证实黄皮酰胺体内抗记忆缺失作用是否也存在手性选择性，并且进一步探讨其作用的机制，用高效液相色谱电化学检测器法测定乙酰胆碱含量并结合行为学实验，比较了（－），（＋）黄皮酰胺对小鼠脑内乙酰胆碱含量及对小鼠记忆障碍的影响。结果表明：（－）黄皮酰胺剂量依赖性地对抗樟柳碱引起的脑皮层、海马、纹状体内乙酰胆碱含量降低，（＋）黄皮酰胺在同样剂量却无此作用。行为学实验也得到相似结果。提示：黄皮酰胺的药理作用存在手性选择性；（－）黄皮酰胺能改善樟柳碱所致的记忆障碍，这与其逆转樟柳碱引起的脑内乙酰胆碱含量降低作用相关。     

黄皮酰胺及其衍生物合成进展

黄皮酰胺是从传统中药黄皮叶中分离出来的一种天然产物,具有良好的保肝和促智活性。为了给生物学评价提供样品,并进行深入的构效关系研究,科研人员展开了大量的合成工作。先后开发了多条全合成路线,针对其多手性中心和多取代基的特点,合成了其全部16个光学异构体,同时,按照结构剖裂原则合成了一系列简化衍生物。     

黄皮叶中黄皮酰胺的分离和结构测定

从黄皮叶中分得一种具有降SGPT活性的新的酰胺类化合物——黄皮酰胺,经光谱分析和化学反应推定其结构为(Ⅰ),并由单晶X衍射确证。     

(-),( )黄皮酰胺对鼠脑内 NMDA- 受体的影响

用［３Ｈ］ＭＫ８０１放射配体竟争结合法测定了（－），（＋）黄皮酰胺对大鼠前脑，海马，皮层等部位突触膜的ＮＭＤＡＲ的作用，以探讨其促智机制。同时用饱和实验分析ｐｏ给药１０ｄ后，小鼠脑内该受体密度的变化。结果表明：（－），（＋）黄皮酰胺对脑内各部位的ＮＭＤＡ受体均无特异亲和力。但（－）黄皮酰胺在体给药１０ｄ后能使小鼠脑内ＮＭＤＡ受体密度显著增高，并呈一定的量效关系。提示黄皮酰胺的药理作用有光学选择性；（－）黄皮酰胺增加脑内ＮＭＤＡ受体密度为其促智作用提供了重要理论依据。     

黄皮酰胺的抑制脂质过氧化和脑保护作用

黄皮酰胺是类似脑复康结构的一种化合物。实验表明po能明显延长小鼠断头后的张口呼吸时间和sc亚硝酸钠225 mg/kg后的动物存活时间。po黄皮酰胺100 mg/kg·bid×3能抑制由p0 50%乙醇(15 ml/kg)诱发小鼠肝脂质过氧化反应,使TBA反应值下降,明显激活肝和脑组织胞浆液中谷胱甘肽过氧化酶的活力。大鼠脑基底动脉条收缩实验结果表明,黄皮酰胺10^-5mol/L可明显抑制由5-HT,PGF_2x和花生四烯酸引起的血管收缩,提示黄皮酰胺有缓解血管痉挛,增加脑血流量的作用。     

Recent advances in the study of (–)clausenamide: chemistry,biological activities and mechanism of action

Clausenamide (clau) is one of seven novel compounds isolated from Clausena lansium (Lour) skeels. Clau is unusual in that it contains 4 chiral centers yielding 8 pairs of enantiomers. After identification of the configuration of these enantiomers, the synthesis of 16 enantiomers, including optically active clau and (+) and (–)clau was carried out. During this study, many stereochemical and synthetic difficulties were solved and the Baldwin principle was updated. Production scale is now sufficient to meet the needs of clinical practice. In a pharmacological study numerous models and indicators showed that (–)clau is the active enantiomer, while (+)clau is inactive and elicits greater toxicity than (–)clau. The principal pharmacological effects of (–)clau are to increase cognition, demonstrated in ten models of memory impairment, as well as to inhibit β-amyloid (Aβ) toxicity, blocking neurofibrillary tangle formation by inhibiting the phosphorylation of tau protein. This anti-dementia effect is characterized by increased synaptic plasticity both in efficacy and in structure and provides new support for the theory that synaptic loss is the main cause of dementia. (–)Clau is considered to be a promising drug candidate for treatment of Alzheimer׳s disease and other neurodegenerative disorders.KEY WORDS: (–)Clausenamide, Enantiomers, Cognition, Alzheimer׳s disease pathology, Tau, High phosphorylation, Synaptic plasticity     

Study on the Nootropic Mechanism of (-)Clausenamide - Influence on the Formation of Synapses in Mouse Brain

The effects of (-)clausenamide (claus) on brain development were studied. Sixty kunming strain weaning mice were divided into 4 groups. One group was served as control administered with normal saline, the other 3 groups were treated with (-)claus 5, 10 and 20mg kg^-1 respectively by gavage once a day for 4 weeks. Results showed that (-)claus at dosage of 5 and 10 mg kg^-1 facilitated learning and memory acquisition in step down and step through tests and increased thickness of cerebral cortex and synapse density significantly in the dentate cells over pyramidel cells in hippocampal region using quantitative technique of synapses analysis. These data provided the morphological basis of the nootropic effect of (-)claus.     

(-),(+)黄皮酰胺对樟柳碱引起的小鼠脑内乙酰胆碱含量降低及记忆障碍的影响

为证实黄皮酰胺体内抗记忆缺失作用是否也存在手性选择性,并且进一步探讨其作用的机制,用高效液相色谱 电化学检测器法测定乙酰胆碱含量并结合行为学实验,比较了(-),(+)黄皮酰胺对小鼠脑内乙酰胆碱含量及对小鼠记忆障碍的影响。结果表明:(-)黄皮酰胺剂量依赖性地对抗樟柳碱引起的脑皮层、海马、纹状体内乙酰胆碱含量降低,(+)黄皮酰胺在同样剂量却无此作用。行为学实验也得到相似结果。提示:黄皮酰胺的药理作用存在手性选择性;(-)黄皮酰胺能改善樟柳碱所致的记忆障碍,这与其逆转樟柳碱引起的脑内乙酰胆碱含量降低作用相关。     

(-),(+)黄皮酰胺对大鼠海马突触传递功能的不同影响

采用细胞外电生理记录法记录了低频刺激所诱发的麻醉大鼠海马齿状回颗粒细胞层群峰电位(PS)并比较了侧脑室注射(-),(+)黄皮酰胺对PS及强直刺激所诱导的长时程增强效应(LTP)作用。结果表明:低剂量(1nmol)时,(-)或(+)黄皮酰胺都对基础状态下的PS没有影响。对LTP(+)黄皮酰胺也无作用,(-)黄皮酰胺表现为增强作用;将剂量提高至4nmol时,(-)黄皮酰胺对基础PS和LTP都有增强作用且对LTP的作用表现出一定的剂量依赖性,(+)黄皮酰胺对PS仍无影响,对LTP有一定的抑制作用。提示黄皮酰胺对海马齿状回突触传递活动的作用具有光学选择性,这一结果有力地支持了(-)黄皮酰胺促智作用的行为学和神经生化学研究结果。