Design and synthesis of isoxazole containing bioisosteres of epibatidine as potent nicotinic acetylcholine receptor agonists

An efficient synthesis of isoxazole containing isosteres of epibatidine is described. The synthesis proceeded from N-tert-butoxycarbonyl (Boc)-exo-2-( methoxycarbonyl)-7-azabicyclo[2.2.1]heptane (9). Compound 9 was reacted wit h the dilithium salt of an appropriately substituted oxime in tetrahydrofur an (THF), Cyclodehydration of the resultant beta-keto oxime and deprotectio n of the N-Boc group in 5 N aqueous HCl afforded the isoxazole containing i sosteres of epibatidine (6-8), The binding affinities of these compounds we re determined at the nicotinic acetylcholine receptor for the displacement of [H-3]cytisine. The unsubstituted isoxazole containing isostere (6) showe d the lower binding potency compared to the 3'-methylisoxazole isostere (7) , Substitution with a phenyl group at the 3'-position of the isoxazole sign ificantly reduced the binding potency. The in vivo toxicological studies of these analogs were also performed, The LD50 of the analogs ranged in the o rder: Me>H>Ph.