New spirocyclic Δ2-isoxazoline derivatives related to selective agonists of α7 neuronal nicotinic acetylcholine receptors

A set of structural analogues of spirocyclic quinuclidinyl-Δ2-isoxazolines, characterized as potent and selective α7 nicotinic agonists, was prepared and assayed for binding affinity at α7 and α4β2 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 α7 subtype when compared with their model compounds. Solely Δ2-isoxazolines 3a, 3b, and 6c maintained a binding affinity in the nanomolar range at the α7 nAChRs (Ki = 230, 420 and 700 nM, respectively). The quaternary ammonium salt 6c retained also a noteworthy α7 vs. α4β2 subtype selectivity, whereas 3a and 3b showed a sharp reduction in selectivity compared with 1a and 1b, their quinuclidinyl higher homologues.

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► Synthesis of spirocyclic Δ2-isoxazoline derivatives as α7 nAChR ligands.
► Binding studies towards α7, α4β2 and α3β4 nAChR subtypes.
►  Δ2isoxazolines 3a, 3b, and 6c exhibited significant α7 nAChR binding affinity in the nanomolar range.
► Conformational analysis and theoretical assessment of SAR by docking in a model of the α7 nAChR.