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 α1a-, α1b-and α1d-adrenoreceptor (α1a-, α1b-and α1d-AR) and at native rat 5-HT1A receptor and for antagonist affinity at α1A-, α1B-and α1D-AR and at α2A/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 α1A and the α1D antagonist affinities were generally lower than the α1a and α1d binding affinities, but not the α1B antagonist affinity, which was similar and sensibly higher compared to α1b binding affinity in the case of F and OMe respectively. This trend confers significant α1B-AR selectivity, in particular, to the 8-methoxy analogue of (S)-WB4101, a new potent (pA2 9.58) α1B-AR antagonist. The S enantiomers of all the tested compounds were proved to act as α1-AR inverse agonists in a vascular model.

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► Alpha1-adrenergic affinity and alpha1 antagonist activity of 8-substituted WB4101 analogues were studied.
► The 8-substituted WB4101 analogues acted as inverse agonists.
► The 8-methoxy analogue was a potent and selective alpha 1B antagonist.