Affinity and activity profiling of unichiral 8-substituted 1,4-benzodioxane analogues of WB4101 reveals a potent and selective α1B- adrenoceptor antagonist

Unichiral 8-substituted analogues of 2-[(2-(2,6-dimethoxyphenoxy)ethyl) aminomethyl]-1,4-benzodioxane (WB4101) were synthesized and tested for binding affinity at cloned human α_1a-, α_1b-and α_1d-adrenoreceptor (α_1a-, α _1b-and α_1d-AR) and at native rat 5-HT_1A receptor and for antagonist affinity at α_1A-, α_1B-and α_1D-AR and at α_2A/D- AR. Among the selected 8-substituents, namely fluorine, chlorine, methoxyl and hydroxyl, only the last caused significant decrease of α₁ binding affinity in comparison with the lead compound. Functional tests on the S isomers confirmed the detrimental effect of OH positioned in proximity to benzodioxane O(1). For the other three substituents (F, Cl, OMe), the α_1A and the α_1D antagonist affinities were generally lower than the α_1a and α_1d binding affinities, but not the α_1B antagonist affinity, which was similar and sensibly higher compared to α_1b binding affinity in the case of F and OMe respectively. This trend confers significant α_1B-AR selectivity, in particular, to the 8-methoxy analogue of (S)-WB4101, a new potent (pA₂ 9.58) α_1B-AR antagonist. The S enantiomers of all the tested compounds were proved to act as α₁-AR inverse agonists in a vascular model.