Development of spiroguanidine-derived α7 neuronal nicotinic receptor partial agonists
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- 作者：Matthew D. Hill ; matthew.hill@bms.com ; Haiquan Fang ; Sivarao V. Digavalli ; Francine L. Healy ; Lizbeth Gallagher ; Debra Post-Munson ; Ping Chen ; Joanne Natale ; Yulia Benitex ; Daniel Morgan ; Nicholas Lodge ; Linda Bristow ; John E. Macor ; Richard E. Olson
- 关键词：α7 nicotinic acetylcholine receptor ; Schizophrenia ; 5-HT3A receptor ; Spiroguanidine ; Immediate early genes
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2017
- 出版时间：1 February 2017
- 年：2017
- 卷：27
- 期：3
- 页码：578-581
- 全文大小：2113 K
- 卷排序：27
文摘
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.