Synthesis of novel epibatidine-related derivatives through 1,3-dipolar cycloaddition of pyridinenitrile oxides

The Delta(2)-isoxazoline derivatives 3a- c and 4a- c, structurally related to epibatidine, and the simplified analogues 5a-c were synthesized by means of a 1,3-dipolar cycloaddition of regioisomeric pyridinenitrile oxides to suitable dipolarophiles. Target compounds were assayed at alpha 4 beta 2 and alpha 7 neuronal acetylcholine receptor (nAChR) subtypes. Competition binding experiments at alpha 4 beta 2 nAChRs showed an overall significant reduction in affinity for the compounds under study in comparison to the reference radioligand [H-3]-epibatidine. On the other hand, compounds 3b, 3c, and 4b exhibited a noticeable affinity for the alpha 7 receptors and 3c showed also a slight degree of alpha 7 over alpha 4 beta 2 selectivity.