Structure-Activity Relationships in 1,4-Benzodioxan-Related Compounds. 6. Role of the Dioxane Unit on Selectivity for Alpha1-Adrenoreceptor Subtypes

WB 4101-related benzodioxans 3-9 were synthesized, and their biological profiles at alpha1-adrenoreceptor subtypes and 5-HT1A serotoninergic receptors were assessed by binding assays in CHO and HeLa cells membranes expressing the human cloned receptors. Furthermore, receptor selectivity of selected benzodioxan derivatives was further determined in functional experiments in isolated rat vas deferens (alpha1A) and aorta (alpha1D) and guinea pig spleen (alpha1B), in additional receptor binding assays in rat cortex membranes containing alpha2-adrenoreceptors and 5-HT2 serotoninergic receptors, and in rat striatum membranes containing D2 dopaminergic receptors. An analysis of the results of receptor binding experiments for benzodioxan-modified derivatives 3-9 showed high affinity and selectivity toward the alpha1a-adrenoreceptor subtype for compounds 3-5 and 7 and a reversed selectivity profile for 9, which was a selective alpha1d antagonist. Furthermore, the majority of structural modifications performed on the prototype 1 (WB 4101) led to a marked decrease in the affinity for 5-HT1A serotoninergic receptors, which may have relevance in the design of selective alpha1A-adrenoreceptor antagonists. The exception to these findings was the chromene derivative 8, which exhibited a 5-HT1A partial agonist profile.