Buchheit K H, Gamse R, Giger R, Hoyer D, Klein F, Klöppner E, Pfannkuche H J, Mattes H
Sandoz Pharma Limited, Basel, Switzerland.
J Med Chem. 1995 Jun 23;38(13):2326-30. doi: 10.1021/jm00013a009.
The design and synthesis of a new class of potent and selective 5-HT4 receptor agonists containing an indole nucleus linked to a carbazimidamide are presented. A conformational study of the 5-HT4 receptor agonists serotonin and zacopride led to the identification of an initial pharmacophore and to the definition of a three-dimensional map of the 5-HT4 agonist recognition site. 1, a representative member of our new class of 5-HT4 receptor agonists, incorporates all reference structural features and matched perfectly with these models. 1 is a highly potent, full agonist at 5-HT4 receptors present in the isolated electrically stimulated guinea pig ileum preparation, with a pD2 value of 8.8, displaying selectivity (ranging from 40- to over 10,000-fold) versus other members of the serotonin receptor family.
本文介绍了一类新型强效且选择性的5-HT4受体激动剂的设计与合成，这类激动剂含有与咔唑咪酰胺相连的吲哚核。对5-HT4受体激动剂血清素和扎考必利的构象研究，确定了一个初始药效团，并定义了5-HT4激动剂识别位点的三维图谱。1作为我们新型5-HT4受体激动剂类别的代表性成员，包含了所有参考结构特征，并与这些模型完美匹配。在分离的电刺激豚鼠回肠制备物中，1是5-HT4受体的高效、完全激动剂，pD2值为8.8，相对于血清素受体家族的其他成员表现出选择性（范围从40倍到超过10000倍）。
