Development of 4-Heteroarylamino-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octanes] as α7 Nicotinic Receptor Agonists

Abstract

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'<i>S</i>,3'<i>R</i>,4'<i>S</i>)-<i>N</i>-(7-bromopyrrolo[2,1-<i>f</i>][1,2,4]triazin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine (<b>20</b>) and (1'<i>S</i>,3'<i>R</i>,4'<i>S</i>)-<i>N</i>-(7-chloropyrrolo[2,1-<i>f</i>][1,2,4]triazin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine (<b>21</b>), 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.