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. 2016 Dec 1;8(1):133-137.
doi: 10.1021/acsmedchemlett.6b00471. eCollection 2017 Jan 12.

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

Matthew D Hill  1 , Haiquan Fang  1 , H Dalton King  1 , Christiana I Iwuagwu  1 , Ivar M McDonald  1 , James Cook  1 , F Christopher Zusi  1 , Robert A Mate  1 , Ronald J Knox  1 , Debra Post-Munson  1 , Amy Easton  1 , Regina Miller  1 , Kimberley Lentz  1 , Wendy Clarke  1 , Yulia Benitex  1 , Nicholas Lodge  1 , Robert Zaczek  1 , Rex Denton  1 , Daniel Morgan  1 , Linda Bristow  1 , John E Macor  1 , Richard Olson  1
Affiliations

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

Matthew D Hill et al. ACS Med Chem Lett. .

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.

Keywords: novel object recognition; quinuclidine; schizophrenia; α7 nAChR.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Examples of known α7 nAChR ligands.
Scheme 1
Scheme 1. Synthetic Route to Spiroimidates 7
Figure 2
Figure 2
Pretreatment with 0.01–0.1 mg/kg spiroimidate 20 or 0.03–0.3 mg/kg spiroimidate 21 30 min prior to training significantly increased the time spent exploring the novel object compared to the familiar object when tested 24 h later.
See this image and copyright information in PMC

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