title: Design and synthesis of isoxazole containing bioisosteres of epibatidine as potent nicotinic acetylcholine receptor agonists.
abstract: 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 with the dilithium salt of an appropriately substituted oxime in tetrahydrofuran (THF). Cyclodehydration of the resultant beta-keto oxime and deprotection of the N-Boc group in 5 N aqueous HCl afforded the isoxazole containing isosteres of epibatidine (6-8). The binding affinities of these compounds were determined at the nicotinic acetylcholine receptor for the displacement of [3H]cystisine. The unsubstituted isoxazole containing isostere (6) showed the lower binding potency compared to the 3'-methylisoxazole isostere (7). Substitution with a phenyl group at the 3'-position of the isoxazole significantly reduced the binding potency. The in vivo toxicological studies of these analogs were also performed. The LD50 of the analogs ranged in the order: Me > H > Ph.
authors.affiliation: Department of Medicinal Chemistry and Pharmaceutics, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73190, USA.
authors.forename: S
authors.initials: S
authors.lastname: Singh
authors.forename: K S
authors.initials: KS
authors.lastname: Avor
authors.forename: B
authors.initials: B
authors.lastname: Pouw
authors.forename: T W
authors.initials: TW
authors.lastname: Seale
authors.forename: G P
authors.initials: GP
authors.lastname: Basmadjian
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000633:toxicity; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D007555:Isoxazoles; D007928:Lethal Dose 50; D051379:Mice; D008958:Models, Molecular; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D011725:Pyridines / Q000737:chemistry* / Q000633:toxicity
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D007555:Isoxazoles; D018733:Nicotinic Antagonists; D011725:Pyridines; C082748:epibatidine