| Literature DB >> 28105289 |
Matthew D Hill1, Haiquan Fang1, H Dalton King1, Christiana I Iwuagwu1, Ivar M McDonald1, James Cook1, F Christopher Zusi1, Robert A Mate1, Ronald J Knox1, Debra Post-Munson1, Amy Easton1, Regina Miller1, Kimberley Lentz1, Wendy Clarke1, Yulia Benitex1, Nicholas Lodge1, Robert Zaczek1, Rex Denton1, Daniel Morgan1, Linda Bristow1, John E Macor1, Richard Olson1.
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'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-HT3A receptor SAR suggested the presence of a steric site that when engaged led to significant loss of affinity at that receptor.Entities:
Keywords: novel object recognition; quinuclidine; schizophrenia; α7 nAChR
Year: 2016 PMID： 28105289 PMCID： PMC5238485 DOI： 10.1021/acsmedchemlett.6b00471
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345