6-甲基-6-氮杂双环[3.2.1]辛烷-3α-醇2,2-二苯基丙酸酯（阿扎丙醇），一种高效的抗毒蕈碱剂。

6-Methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (azaprophen), a highly potent antimuscarinic agent.

作者信息

Carroll F I, Abraham P, Parham K, Griffith R C, Ahmad A, Richard M M, Padilla F N, Witkin J M, Chiang P K

出版信息

J Med Chem. 1987 May;30(5):805-9. doi: 10.1021/jm00388a010.

Abstract

The synthesis and antimuscarinic properties of 6-methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (1, azaprophen) are described. Azaprophen is 50 times more potent than atropine as an antimuscarinic agent as measured by the inhibition of acetylcholine-induced contraction of guinea pig ileum and is more than 1000 times better than atropine in its ability to block alpha-amylase release from pancreatic acini cells induced by carbachol. In addition, azaprophen is 27 times more potent than atropine as an inhibitor of binding of [N-methyl-3H]scopolamine to muscarinic receptors, with human IMR-30 neuroblastoma cells. The potencies of azaprophen and atropine in altering operant behavior were similar. The structural features of 1 are compared to the standard anticholinergic drugs atropine and quinuclidinyl benzilate by using energy calculations and molecular modelling studies. A modification of the pharmacophore model hypothesis for cholinergic agents is suggested.

摘要

描述了6-甲基-6-氮杂双环[3.2.1]辛烷-3α-醇2,2-二苯基丙酸酯（1，氮杂丙芬）的合成及其抗毒蕈碱特性。通过抑制乙酰胆碱诱导的豚鼠回肠收缩来测定，氮杂丙芬作为抗毒蕈碱剂的效力比阿托品高50倍，并且在阻断卡巴胆碱诱导的胰腺腺泡细胞释放α-淀粉酶的能力方面比阿托品强1000倍以上。此外，在人IMR-30神经母细胞瘤细胞中，氮杂丙芬作为[N-甲基-3H]东莨菪碱与毒蕈碱受体结合的抑制剂，其效力比阿托品高27倍。氮杂丙芬和阿托品在改变操作性行为方面的效力相似。通过能量计算和分子建模研究，将1的结构特征与标准抗胆碱能药物阿托品和奎宁环基苯甲酸酯进行了比较。提出了对胆碱能药物药效团模型假说的一种修正。