New spirocyclic Delta(2)-isoxazoline derivatives related to selective agonists of alpha7 neuronal nicotinic acetylcholine receptors.

A set of structural analogues of spirocyclic quinuclidinyl-D2-isoxazolines, characterized as potent and selective a7 nicotinic agonists, was prepared and assayed for binding affinity at a7 and a4b2 neuronal nicotinic acetylcholine receptors (nAChRs). The investigated derivatives (3ae3c, 4ae4c, 5ae5c, 6ae6c, and 7ae7c), synthesized via the 1,3-dipolar cycloaddition of nitrile oxides to suitable dipolarophiles, showed an overall reduced affinity at the a7 subtype when compared with their model compounds. Solely D2-isoxazolines 3a, 3b, and 6c maintained a binding affinity in the nanomolar range at the a7 nAChRs (Ki ¼ 230, 420 and 700 nM, respectively). The quaternary ammonium salt 6c retained also a noteworthy a7 vs. a4b2 subtype selectivity, whereas 3a and 3b showed a sharp reduction in selectivity compared with 1a and 1b, their quinuclidinyl higher homologues.