QSAR study for a novel series of ortho disubstituted phenoxy analogues of α1-adrenoceptor antagonist WB4101

On the basis of the affinities at the α_1a-, α_1b- and α_1d-adrenoceptors and the 5-HT_1A receptor of a previous series of sixteen 2-[(2-phenoxyethyl)aminomethyl]-1,4-benzodioxanes ortho monosubstituted at the phenoxy moiety, a number of ortho disubstituted analogues were designed, synthesized in both the enantiomeric forms and tested in binding assays on the same receptors. The affinity values of the new compounds 1-11 were compared with those of the enantiomers of the 2,6-dimethoxyphenoxy analogue, the well-known α1 antagonist WB4101, and of the ortho monosubstituted derivatives, suggesting some distinctive aspects of the interaction of the phenoxy moiety, in particular with the α_1a-AR and the 5-HT_1A receptor, of the monosubstituted and the disubstituted compounds. A classical quantitative structure-activity relationship (Hansch) analysis was applied to the whole set of the S enantiomers of the ortho mono- and disubstituted WB4101 analogues (26 compounds), finding a very good correlation for the α_1a affinity. For this latter, a significant parabolic relationship was also found with the volume of the two ortho substituents. Diametrically opposite, the same relationships for the 5-HT_1A exhibit low or insignificant correlation coefficients.