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

A group of novel tricyclic Δ2-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 α4β2 and α7 neuronal acetylcholine receptors (nAChRs). The results of competition binding experiments indicated for the new derivatives a reduction of the affinity at the α4β2 subtype in comparison with the reference molecules, coupled with an overall negligible affinity at the α7 subtype. The binding mode of the bromo-Δ2-isoxazolines 4b and 7b, which were the highest affinity ligands in the series (Ki = 0.92 and 0.75 μM, respectively), was analyzed by applying a recently developed model of the α4β2 nAChRs.