QSAR study for a novel series of ortho disubstituted phenoxy analogues of α 1-adrenoceptor antagonist WB4101

Abstract

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.