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

Abstract

The ??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 ??4??2 and ??7 neuronal acetylcholine receptor (nAChR) subtypes. Competition binding experiments at ??4??2 nAChRs showed an overall significant reduction in affinity for the compounds under study in comparison to the reference radioligand [3H]-epibatidine. On the other hand, compounds 3b, 3c, and 4b exhibited a noticeable affinity for the ??7 receptors and 3c showed also a slight degree of ??7 over ??4??2 selectivity. ?? ARKAT.