Design and Synthesis of a New Series of 4-Heteroarylamino-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octanes as α7 Nicotinic Receptor Agonists. 1. Development of Pharmacophore and Early Structure - Activity Relationship

The design and synthesis of a series of quinuclidine-containing spirooxazolidines (spiroimidates) and their utility as alpha 7 nicotinic acaylcholine receptor partial agonists are described. Selected members of the series demonstrated excellent selectivity for alpha 7 over the highly homologous 5-HT3A receptor. Modification of the N-spiroirnidate heterocycle substituent led to (13,2R,4S)-N-isoquinolin-3-yl)-4'H-4-azaspirci[bicyclo [2.2.2] octane-2,5'oxazol]-2'-aynine (BMS-902483), a potent alpha 7 partial agonist, which improved cognition in preclinical rodent models.