We describe the synthesis of quinuclidine-containing spiroimidates and their utility as α7 nicotinic acetylcholine receptor (nAChR) partial agonists. A convergent synthetic route allowed for rapid SAR investigation and provided a diverse set of fused 6,5-heteroaryl analogs. Two potent and selective α7 nAChR partial agonists, (1′S,3′R,4′S)-N-(7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (20) and (1′S,3′R,4′S)-N-(7-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (21), were identified. Both agonists improved cognition in a preclinical rodent model of learning and memory. Additionally, 5-HT_3A receptor SAR suggested the presence of a steric site that when engaged led to significant loss of affinity at that receptor.

中文翻译：

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4-杂芳基氨基-1'-氮杂螺[恶唑-5,3'-双环[2.2.2]辛烷]作为α7烟碱受体激动剂的开发


我们描述了含有奎宁环的螺亚胺酯的合成及其作为 α7 烟碱乙酰胆碱受体 (nAChR) 部分激动剂的用途。聚合合成路线允许快速 SAR 研究并提供多种融合的 6,5-杂芳基类似物。两种有效且选择性的 α7 nAChR 部分激动剂，(1′ S ,3′ R ,4′ S )- N -(7-bromopyrrolo[2,1- f ][1,2,4]triazin-4-yl)- 4H-1'-氮杂螺[恶唑-5,3'-双环[2.2.2]辛烷]-2-胺( 20 )和(1 'S , 3'R ,4 'S ) -N- (7-氯吡咯) [2,1- f ][1,2,4]三嗪-4-基)-4H-1'-氮杂螺[恶唑-5,3'-双环[2.2.2]辛烷]-2-胺 ( 21 ) ，被识别出来。两种激动剂都能改善临床前啮齿动物学习和记忆模型的认知能力。此外，5-HT _3A受体 SAR 表明存在一个空间位点，当该位点参与时会导致该受体的亲和力显着丧失。