Differential neuropsychopharmacological influences of naturally occurring tropane alkaloids anisodamine versus scopolamine
Differential neuropsychopharmacological influences of naturally occurring tropane alkaloids anisodamine versus scopolamine
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DOI：
10.1016/j.neulet.2008.07.048
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发表时间：
2008-10
影响因子：
2.5
通讯作者：
Weiwei Zhang;Mingke Song;Yong-yao Cui;Hao Wang;Hong-Zhuan Chen
中科院分区：
文献类型：
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作者：
Weiwei Zhang;Mingke Song;Yong-yao Cui;Hao Wang;Hong-Zhuan Chen
山莨菪碱和东莨菪碱是两种天然存在的莨菪烷类生物碱，结构上有一个OH基团不同，在临床和基础研究中被公认为是毒蕈碱型乙酰胆碱受体（mAChR）拮抗剂。然而，与东莨菪碱相比，山莨菪碱中枢作用的实验证据是有限的和矛盾的。本研究采用Morris水迷宫实验、长时程增强（LTP）记录和受体放射性配体结合实验，探讨山莨菪碱和东莨菪碱对神经精神药理作用的差异及其可能机制。山莨菪碱的剂量比东莨菪碱高10-40倍，并不像东莨菪碱那样产生任何空间认知缺陷，但在重复高剂量时倾向于改善认知。然后采用体内LTP预测全身给药后毒蕈碱拮抗剂的BBB通透性。与东莨菪碱相反，山莨菪碱在高剂量40倍时对大鼠海马CA 1区LTP的形成无影响。此外，受体放射性配体结合试验（RRLBA）显示山莨菪碱与小鼠脑mAChR的结合亲和力远低于东莨菪碱。结果表明，山莨菪碱不损害认知，也不降低LTP主要是由于其不良的血脑屏障通透性。本工作丰富了对托烷类生物碱构效关系的认识，同时也为临床合理用药提供了依据。
Two naturally occurring tropane alkaloids, anisodamine and scopolamine, structurally dissimilar in one OH group, are well established as muscarinic acetylcholine receptor (mAChR) antagonists in clinic and basic research. However, experimental evidence for central effects of anisodamine is limited and conflicting compared with that of scopolamine. In the present study, Morris water maze test, long-term potentiation (LTP) recording and receptor radioligand binding assays were used to explore the disparity in neuropsychopharmacological influences of anisodamine versus scopolamine and possible mechanisms. Anisodamine, at 10–40-fold higher doses than those of scopolamine, did not produce any spatial cognitive deficits as scopolamine, but tended to improve cognition at the repeated high doses. LTP in vivo was then adopted to predict BBB permeability of the muscarinic antagonists following systemic drug administration. Contrary to scopolamine, anisodamine did not influence the formation of LTP in the CA1region of rat hippocampus at 40-fold higher dose than that of scopolamine. Additionally, receptor radioligand binding assays (RRLBA) revealed that the binding affinity of anisodamine to mice brain mAChR was much lower than that of scopolamine. The findings suggested that anisodamine did not impair cognition nor depress LTP primarily due to its poor BBB permeability. This work enlarged knowledge of structure–activity relationship among tropane alkaloids, meanwhile providing evidence for more reasonable drug prescription in clinic.