Novel tricyclic Delta(2)-isoxazoline and 3-oxo-2-methyl-isoxazolidine derivatives: Synthesis and binding affinity at neuronal nicotinic acetylcholine receptor subtypes

作者：Dallanoce Clelia^*; Frigerio Fabio; Martelli Giuliana; Grazioso Giovanni; Matera Carlo; Pome Diego Yuri; Pucci Luca; Clementi Francesco; Gotti Cecilia; De Amici Marco

来源：Bioorganic & Medicinal Chemistry, 2010, 18(12): 4498-4508.

DOI：10.1016/j.bmc.2010.04.065

• Delta(2)-Isoxazoline and 3-oxo-isoxazolidine derivatives
• Neuronal nicotinic acetylcholine receptors
• Cytisine and ferruginine analogues
• Binding affinity
• Molecular modeling

A group of novel tricyclic Delta(2)-isoxazolines (4b, 5b, 7a-b, and 8a-b) and 3-oxo-isoxazolidines (6a-b and 9a-b), structurally related to cytisine or norferruginine, was prepared through 1,3-dipolar cycloadditions involving suitable olefins and bromonitrile oxide. The target compounds were assayed at alpha 4 beta 2 and alpha 7 neuronal acetylcholine receptors (nAChRs). The results of competition binding experiments indicated for the new derivatives a reduction of the affinity at the alpha 4 beta 2 subtype in comparison with the reference molecules, coupled with an overall negligible affinity at the alpha 7 subtype. The binding mode of the bromo-Delta(2)-isoxazolines 4b and 7b, which were the highest affinity ligands in the series (K-i = 0.92 and 0.75 mu M, respectively), was analyzed by applying a recently developed model of the alpha 4 beta 2 nAChRs.

• 出版日期2010-6-15