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Eur J Med Chem. 2010 Dec;45(12):5594-601. doi: 10.1016/j.ejmech.2010.09.009. Epub 2010 Sep 17.

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

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Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.


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.

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