Synthesis of novel chiral Δ2-isoxazoline derivatives related to ABT-418 and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes

The enantiopure diastereomeric Δ2-isoxazoline derivatives (2S,5′R)-5a–10a and (2S,5′S)-5b, (2S,5′S)-9b, (2S,5′S)-11b, which are structural analogues of both ABT-418 2 and oxyimino ethers (S)-3 and (Z)-(S)-4, were synthesized through cycloaddition reactions involving nitrile oxides as 1,3-dipoles and (S)-N-Boc-2-vinylpyrrolidine-13 as the dipolarophile. The absolute configuration was unequivocally assigned to target compounds by means of an X-ray analysis. The derivatives under study were assayed at neuronal acetylcholine nicotinic receptors (nAChRs), where they showed a meaningful reduction in affinity at the heteromeric α4β2 subtype when compared to the reference molecules. Conversely, anti (2S,5′S)-5b and syn (2S,5′R)-10a isomers showed an affinity for the α7 nAChRs comparable to that observed for the model compound ABT-418.

Graphical abstractA group of novel Δ2-isoxazolines structurally related to oxyimino ethers and to the isoxazole nicotinic agonist ABT-418 were prepared and assayed for their binding affinity at α4β2 and α7 nicotinic acetylcholine receptor subtypes.Figure optionsDownload full-size imageDownload as PowerPoint slide