Dallanoce_2010_Eur.J.Med.Chem_45_5594

The enantiopure diastereomeric Delta2-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 alpha4beta2 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 alpha7 nAChRs comparable to that observed for the model compound ABT-418.