Yu A Y, Sun C
Department of Pharmacology, Shanghai Second Medical University, China.
Zhongguo Yao Li Xue Bao. 1990 Sep;11(5):394-400.
Bao gong teng A (BGT-A), a cholinergic tropane, was first separated from Erycibe obtusifolia Benth in China in 1978. 6 beta-Acetoxy nortropane (6 beta-AN), a new tropane analogue of BGT-A, was synthesized in 1983, in our university. Tropanes are generally known as M-cholinoceptor blockers, but 6 beta-AN is a M-cholinoceptor agonist. The levorotatory 6 beta-AN is an active form that has been proved in biological and competitive binding test. The receptor binding experiment of 6 beta-AN were compared with those of M-receptor agonists (oxotremorine, carbachol, BGT-A and pilocarpine) and antagonists (pirenzepine, gallamine, atropine, scopolamine and anisodamine) on 4 different target tissues. The affinity order (pKi) of 6 beta-AN to 4 tissues (heart, cortex-hippocampus, ileal longitudinal muscle and iris) were 7.7, 6.8, 5.6 and 5.5, respectively. 6 beta-AN improved performances of mice in three-arm maze. Down-step tests suggested some potential nootropic effect. 6 beta-AN decreased the heart rate and cardiac contraction, increased the ileal longitudinal muscle contraction and pupil constriction. All above mentioned biological effects were antagonized by atropine. In receptor kinetics studies, we found marked discrepancy between pD2 and pKi. "The stronger the agonist, the larger the difference" suggest that different biological amplification systems are involved. Study on the receptor regulation showed surprisingly a specific subtype receptor regulation and 6 beta-AN gave a downward regulation on M2-R subtype only. Our data show that 6 beta-AN gallamine, oxotremorine and carbachol are M2-R subtype selective agents, while pirenzepine and pilocarpine are M1-R subtype selective agents.
包公藤甲素（BGT-A）是一种胆碱能托烷类生物碱，1978年首次在中国从丁公藤中分离得到。1983年，我校合成了一种新的BGT-A托烷类似物6β-乙酰氧基去甲托烷（6β-AN）。托烷类化合物通常被认为是M胆碱受体阻断剂，但6β-AN是一种M胆碱受体激动剂。左旋6β-AN是一种活性形式，已在生物学和竞争性结合试验中得到证实。将6β-AN的受体结合实验与M受体激动剂（氧化震颤素、卡巴胆碱、BGT-A和毛果芸香碱）和拮抗剂（哌仑西平、加拉明、阿托品、东莨菪碱和山莨菪碱）在4种不同靶组织上的实验进行了比较。6β-AN对4种组织（心脏、皮层-海马、回肠纵肌和虹膜）的亲和力顺序（pKi）分别为7.7、6.8、5.6和5.5。6β-AN改善了小鼠在三臂迷宫中的表现。下行试验表明其具有一些潜在的促智作用。6β-AN降低心率和心脏收缩力，增加回肠纵肌收缩和瞳孔收缩。上述所有生物学效应均被阿托品拮抗。在受体动力学研究中，我们发现pD2和pKi之间存在明显差异。“激动剂越强，差异越大”表明涉及不同的生物放大系统。受体调节研究令人惊讶地显示出一种特异性亚型受体调节，6β-AN仅对M2-R亚型产生下调作用。我们的数据表明，6β-AN、加拉明、氧化震颤素和卡巴胆碱是M2-R亚型选择性药物，而哌仑西平和毛果芸香碱是M1-R亚型选择性药物。
