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

Abstract

A number of ( S)- and ( R)-2-[(2-phenoxyethyl)aminomethyl]-1,4-benzodioxanes unsubstituted or ortho monosubstituted at the phenoxy moiety were synthesized and tested in binding assays on the α 1a-AR, α 1b-AR, α 1d-AR and the 5-HT 1A receptor. The affinity values of the new compounds 1– 16 were compared with those of the enantiomers of the 2,6-dimethoxyphenoxy analogue, the well-known α 1 antagonist WB4101, finding that the unsubstituted derivative ( S)- 1 and the o-methyl, the o- t-butyl, the o-fluoro and the o-methoxy derivatives, ( S)- 2, ( S)- 4, ( S)- 8 and ( S)- 16, respectively, display a significantly specific 5-HT 1A affinity, very close, with the exception of ( S)- 4, to the almost nanomolar one of ( S)-WB4101. Otherwise, sensible affinity decreases were recorded for the three α 1-AR subtypes. A classical quantitative structure–activity relationship (Hansch) analysis was successfully applied to compounds ( S)- 1 to ( S)- 16 and ( S)-WB4101 to rationalize such binding data.