Dallanoce_2011_Eur.J.Med.Chem_46_5790

A set of structural analogues of spirocyclic quinuclidinyl-Delta(2)-isoxazolines, characterized as potent and selective alpha7 nicotinic agonists, was prepared and assayed for binding affinity at alpha7 and alpha4beta2 neuronal nicotinic acetylcholine receptors (nAChRs). The investigated derivatives (3a-3c, 4a-4c, 5a-5c, 6a-6c, and 7a-7c), synthesized via the 1,3-dipolar cycloaddition of nitrile oxides to suitable dipolarophiles, showed an overall reduced affinity at the alpha7 subtype when compared with their model compounds. Solely Delta(2)-isoxazolines 3a, 3b, and 6c maintained a binding affinity in the nanomolar range at the alpha7 nAChRs (K(i) = 230, 420 and 700 nM, respectively). The quaternary ammonium salt 6c retained also a noteworthy alpha7 vs. alpha4beta2 subtype selectivity, whereas 3a and 3b showed a sharp reduction in selectivity compared with 1a and 1b, their quinuclidinyl higher homologues.