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 a1a-, a1b-and a1d-adrenoreceptor (a1a-, a1b-and a1d-AR) and at native rat 5-HT1A receptor and for antagonist affinity at a1A-, a1B-and a1D-AR and at a2A/D-AR. Among the selected 8 substituents, namely fluorine, chlorine, methoxyl and hydroxyl, only the last caused significant decrease of a1 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 a1A and the a1D antagonist affinities were generally lower than the a1a and a1d binding affinities, but not the a1B antagonist affinity, which was similar and sensibly higher compared to a1b binding affinity in the case of F and OMe respectively. This trend confers significant a1B-AR selectivity, in particular, to the 8-methoxy analogue of (S)-WB4101, a new potent (pA2 9.58) a1B-AR antagonist. The S enantiomers of all the tested compounds were proved to act as a1-AR inverse agonists in a vascular model.