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 α(1) 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 (pA(2) 9.58) α(1B)-AR antagonist. The S enantiomers of all the tested compounds were proved to act as α(1)-AR inverse agonists in a vascular model.