Synthesis and alpha-blocl«ing activity of some cyclicand opened analogues of WB 4101 (-)

The synthesis of some cyclic and opened analogues of 2-(2,6-dimethoxyphenoxyethylaminomethyl)-1,4-benzodioxane (1, WB 4101) is described. The blocking activity of 1-5 was determined on the pre- and postsynaptic alpha-adrenoceptors of isolated rat vas deferens to investigate the structural requirements for competitive alpha-adrenoceptor occupancy by antagonists of the benzodioxane class. The activities of 1-5 at the presynapticalpha-adrenoceptor were not signiflcantly different whereas there were differences among the compounds of at least two orders of magnitudeat the postsynaptic alpha-adrenoceptor. This clearly indicates that the shuctural requirements at the presynaplic receptor level are less restriclive than those required by the postsynaptic alpha-adrenoceptor. The symmetric analogues 3 and 4 were significantly weaker postsynaplic alpha-antagonists compared to 1. On the other hand, 2 and 5 displayed a very high postsynaptic activity, almost comparable to that of 1. Thèse findingi might suggest that the antagonists of the benzodioxane class do not bind at two identical aromalic sites symmetrically arranged around the anionic site of the alpha-adrenoceptor. Indeed, they might indicate that the benzodioxane binding site(s) incorporates two areas with very similar but not identical strLrctural requirements. Furthermore, the very high activity of 5 may suggest that the benzodioxane nucleus is not essential to activity.