New spirocyclic \u3942-isoxazoline derivatives related to selective agonists of \u3b17 neuronal nicotinic acetylcholine receptors

A set of structural analogues of spirocyclic quinuclidinyl-\u3942-isoxazolines, characterized as potent and selective \u3b17 nicotinic agonists, was prepared and assayed for binding affinity at \u3b17 and \u3b14\u3b22 neuronal nicotinic acetylcholine receptors (nAChRs). The investigated derivatives (3a\u20133c, 4a\u20134c, 5a\u20135c, 6a\u20136c, and 7a\u20137c), synthesized via the 1,3-dipolar cycloaddition of nitrile oxides to suitable dipolarophiles, showed an overall reduced affinity at the \u3b17 subtype when compared with their model compounds. Solely \u3942-isoxazolines 3a, 3b, and 6c maintained a binding affinity in the nanomolar range at the \u3b17 nAChRs (Ki = 230, 420 and 700 nM, respectively). The quaternary ammonium salt 6c retained also a noteworthy \u3b17 vs. \u3b14\u3b22 subtype selectivity, whereas 3a and 3b showed a sharp reduction in selectivity compared with 1a and 1b, their quinuclidinyl higher homologues