Targacept, Inc., 100 North Main Street, Winston-Salem, NC 27101, USA.
Bioorg Med Chem Lett. 2013 Jul 1;23(13):3927-34. doi: 10.1016/j.bmcl.2013.04.058. Epub 2013 May 1.
A novel series of α4β2 nAChR agonists lacking common pyridine or its bioisosteric heterocycle have been disclosed. Essential pharmacophoric elements of the series are exocyclic carbonyl moiety as a hydrogen bond acceptor and secondary amino group within diaza- or azabicyclic scaffold. Computer modeling studies suggested that molecular shape of the ligand also contributes to promotion of agonism. Proof of concept for improving working memory performance in a novel object recognition task has been demonstrated on a representative of the series, 3-propionyl-3,7-diazabicyclo[3.3.0]octane (34).
现已披露了一系列新型的α4β2 nAChR 激动剂，它们不含常见的吡啶或其生物等排杂环。该系列的基本药效基团是作为氢键受体的环外羰基部分以及二氮杂或氮杂双环支架内的仲氨基。计算机建模研究表明，配体的分子形状也有助于促进激动作用。以该系列的代表性化合物 3-丙酰基-3,7-二氮杂双环[3.3.0]辛烷（34）为例，已经证明了在新型物体识别任务中改善工作记忆性能的概念验证。
