ACS Medicinal Chemistry Letters p. 133 - 137 (2017)
Update date:2022-08-04
Topics:
Hill, Matthew D.
Fang, Haiquan
King, H. Dalton
Iwuagwu, Christiana I.
McDonald, Ivar M.
Cook, James
Zusi, F. Christopher
Mate, Robert A.
Knox, Ronald J.
Post-Munson, Debra
Easton, Amy
Miller, Regina
Lentz, Kimberley
Clarke, Wendy
Benitex, Yulia
Lodge, Nicholas
Zaczek, Robert
Denton, Rex
Morgan, Daniel
Bristow, Linda
Macor, John E.
Olson, Richard
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.
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