Structure-activity relationships in 1,4-benzodioxan-related compounds. 6. Role of the dioxane unit on selectivity for alpha(1)-adrenoreceptor subtypes

WB 4101-related benzodioxans 3-9 were synthesized, and their biological pro files at alpha(1)-adrenoreceptor subtypes and 5-HT1A serotoninergic recepto rs were assessed by binding assays in CHO and HeLa cells membranes expressi ng the human cloned receptors. Furthermore, receptor selectivity of selecte d benzodioxan derivatives was further determined in functional experiments in isolated rat vas deferens ((alpha(1A)) and aorta (alpha(1D)) and guinea pig spleen (alpha(1B)), in additional receptor binding assays in rat cortex membranes containing alpha(2)-adrenoreceptors and 5-HT2 serotoninergic rec eptors, and in rat striatum membranes containing D-2 dopaminergic receptors . An analysis of the results of receptor binding experiments for benzodioxa n-modified derivatives 3-9 showed high affinity and selectivity toward the alpha(1a)-adrenoreceptor subtype for compounds 3-5 and 7 and a reversed sel ectivity profile for 9, which was a selective aid antagonist. Furthermore, the majority of structural modifications performed on the prototype 1 (WB 4 101) led to a marked decrease in the affinity for 5-HT1A serotoninergic rec eptors, which may have relevance in the design of selective alpha(1A)-adren oreceptor antagonists. The exception to these findings was the chromene der ivative 8, which exhibited a 5-HT1A partial agonist profile.