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Development of spiroguanidine-derived α7 neuronal nicotinic receptor partial agonists
Matthew D Hill1, Haiquan Fang1, Sivarao V Digavalli1
1Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Abstract:
We describe the synthesis of quinuclidine-containing spiroguanidines and their utility as α7 neuronal nicotinic acetylcholine receptor (nAChR) partial agonists. The convergent synthetic route developed for this study allowed for rapid SAR investigation and provided access to a structurally diverse set of analogs. A potent and selective α7 nAChR partial agonist, N-(6-methyl-1,3-benzoxazol-2-yl)-3',5'-dihydro-4-azaspiro[bicyclo[2.2.2]octane-2,4'-imidazole]-2'-amine (BMS-910731, 16), was identified. This compound induced immediate early genes c-fos and Arc in a preclinical rodent model of α7 nAChR-derived cellular activation and plasticity. Importantly, the ability to incorporate selectivity for the α7 nACh receptor over the 5-HT3A receptor in this series suggested a significant difference in steric requirements between the two receptors.
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