Angeli P, Brasili L, Cantalamessa F, Marucci G, Wess J
Dipartimento di Scienze Chimiche, Università di Camerino, Italy.
Naunyn Schmiedebergs Arch Pharmacol. 1990 Dec;342(6):625-9. doi: 10.1007/BF00175704.
The agonistic potencies of (+/-)muscarine, (+/-)cis-2-methyl-5- [(dimethylamino)methyl]-1,3-oxathiolane methiodide (cis-oxathiolane) and its two enantiomers were determined at muscarinic M1 and M2 receptors in the pithed rat. In non-pretreated animals, i.v. administration of these agents produced bradycardic effects mediated by cardiac M2 receptors followed by increases in heart rate mediated by M1 receptors in sympathetic ganglia. As these responses have been shown to partly overlap, "true" M1 and M2 potencies were determined after selective blockade of M1 and M2 receptors by pirenzepine and methoctramine, respectively. A similar rank order of agonist potencies was obtained at M1 and M2 receptors: (+)cis-oxathiolane greater than (+/-)cis-oxathiolane greater than (+/-)muscarine greater than (-)cis-oxathiolane. At both receptor subtypes, (+)cis-oxathiolane was considerably more potent (ca. 30-fold) than its corresponding (-) enantiomer indicating that the agonist binding sites of the two receptor subtypes may have similar stereochemical properties. While (+/-)muscarine showed similar potencies at M1 and M2 receptors, racemic cis-oxathiolane and its two enantiomers showed a slight selectivity (3-7 fold) for M1 receptors indicating the potential usefulness of these compounds in the development of selective M1 receptor agonists.
在脊髓麻醉大鼠的毒蕈碱M1和M2受体上测定了（±）毒蕈碱、（±）顺式-2-甲基-5-[(二甲氨基)甲基]-1,3-氧硫杂环戊烷甲碘化物（顺式氧硫杂环戊烷）及其两种对映体的激动活性。在未经预处理的动物中，静脉注射这些药物会产生由心脏M2受体介导的心动过缓效应，随后是由交感神经节中的M1受体介导的心率增加。由于这些反应已被证明部分重叠，因此分别用哌仑西平和甲奥氮平选择性阻断M1和M2受体后，测定了“真正的”M1和M2活性。在M1和M2受体上获得了相似的激动剂活性顺序：（+）顺式氧硫杂环戊烷＞（±）顺式氧硫杂环戊烷＞（±）毒蕈碱＞（-）顺式氧硫杂环戊烷。在两种受体亚型上，（+）顺式氧硫杂环戊烷的活性都比其相应的（-）对映体强得多（约30倍），这表明两种受体亚型的激动剂结合位点可能具有相似的立体化学性质。虽然（±）毒蕈碱在M1和M2受体上表现出相似的活性，但外消旋顺式氧硫杂环戊烷及其两种对映体对M1受体表现出轻微的选择性（3-7倍），这表明这些化合物在开发选择性M1受体激动剂方面具有潜在用途。
