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 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.
Singh
S
S
Department of Medicinal Chemistry and Pharmaceutics, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73190, USA.
Avor
K S
KS
Pouw
B
B
Seale
T W
TW
Basmadjian
G P
GP
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
D019086:Bridged Bicyclo Compounds, Heterocyclic; D007555:Isoxazoles; D018733:Nicotinic Antagonists; D011725:Pyridines; C082748:epibatidine