Design and Synthesis of Isoxazole Containing Bioisosteres of Epibatidine as Potent Nicotinic Acetylcholine Receptor Agonists

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概要

• 論文の詳細を見る

• 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 β-keto oxime and deprotection of the N-Boc group in 5N 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]cytisine. 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 LD_<50> of the analogs ranged in the order : Me>H>Ph.

• 公益社団法人日本薬学会の論文
• 1999-10-15

著者

• Singh Sanjewon

  Department Of Medcinal Chemistry I. M. S. Banaras Hindu University

• Singh Satendra

  Department Of Medicinal Chemistry And Pharmaceutics College Of Pharmacy University Of Oklahoma Healt

• AVOR Kwasi

  Department of Medicinal Chemistry and Pharmaceutics, College of Pharmacy University of Oklahoma Heal

• POUW Buddy

  Department of Medicinal Chemistry and Pharmaceutics, College of Pharmacy University of Oklahoma Heal

• SEALE Thomas

  Department of Pediatrics, Psychiatry and Behavioral Science, College of Medicine University of Oklah

• BASMADJIAN Garo

  Department of Medicinal Chemistry and Pharmaceutics, College of Pharmacy University of Oklahoma Heal

• Pouw Buddy

  Department Of Medicinal Chemistry And Pharmaceutics College Of Pharmacy University Of Oklahoma Healt

• Avor Kwasi

  Department Of Medicinal Chemistry And Pharmaceutics College Of Pharmacy University Of Oklahoma Healt

• Seale Thomas

  Department Of Pediatrics Psychiatry And Behavioral Science College Of Medicine University Of Oklahom

• Basmadjian Garo

  Department Of Medicinal Chemistry And Pharmaceutics College Of Pharmacy University Of Oklahoma Healt

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• Design and Synthesis of Isoxazole Containing Bioisosteres of Epibatidine as Potent Nicotinic Acetylcholine Receptor Agonists
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