QSAR study for a novel series of ortho disubstituted phenoxy analogues of a1-adrenoceptor antagonist WB4101

On the basis of the affinities at the a1a-, a1b- and a1d-adrenoceptors and the 5-HT1A receptor of a previous series of sixteen 2-[(2-phenoxyethyl)aminomethyl]-1,4-benzodioxanes ortho monosubstituted at the phenoxy moiety, a no. of ortho disubstituted analogs were designed, synthesized in both the enantiomeric forms and tested in binding assays on the same receptors. The affinity values of the new compds. 1-11 were compared with those of the enantiomers of the 2,6-dimethoxyphenoxy analog, the well-known a1 antagonist WB4101, and of the ortho monosubstituted derivs., suggesting some distinctive aspects of the interaction of the phenoxy moiety, in particular with the a1a-AR and the 5-HT1A receptor, of the monosubstituted and the disubstituted compds. A classical quant. structure-activity relationship (Hansch) anal. was applied to the whole set of the S enantiomers of the ortho mono- and disubstituted WB4101 analogs (26 compds.), finding a very good correlation for the a1a affinity. For this latter, a significant parabolic relationship was also found with the vol. of the two ortho substituents. Diametrically opposite, the same relationships for the 5-HT1A exhibit low or insignificant correlation coeffs