title: QSAR study for a novel series of ortho disubstituted phenoxy analogues of alpha1-adrenoceptor antagonist WB4101.
abstract: On the basis of the affinities at the alpha1a-, alpha1b- and alpha1d-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 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 alpha1 antagonist WB4101, and of the ortho monosubstituted derivatives, suggesting some distinctive aspects of the interaction of the phenoxy moiety, in particular with the alpha1a-AR and the 5-HT1A 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 alpha1a 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-HT1A exhibit low or insignificant correlation coefficients.
authors.affiliation: Istituto di Chimica Farmaceutica e Tossicologica, Università di Milano, viale Abruzzi 42, I-20131 Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pallavicini
authors.forename: L
authors.initials: L
authors.lastname: Fumagalli
authors.forename: M
authors.initials: M
authors.lastname: Gobbi
authors.forename: C
authors.initials: C
authors.lastname: Bolchi
authors.forename: S
authors.initials: S
authors.lastname: Colleoni
authors.forename: B
authors.initials: B
authors.lastname: Moroni
authors.forename: A
authors.initials: A
authors.lastname: Pedretti
authors.forename: C
authors.initials: C
authors.lastname: Rusconi
authors.forename: G
authors.initials: G
authors.lastname: Vistoli
authors.forename: E
authors.initials: E
authors.lastname: Valoti
mesh_terms: D018674:Adrenergic Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004146:Dioxanes / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D006801:Humans; D008744:Methylamines / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism
chemical_list: D018674:Adrenergic Antagonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D004146:Dioxanes; D008744:Methylamines; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane