QSAR study for a novel series of ortho disubstituted phenoxy analogues of alpha1-adrenoceptor antagonist WB4101

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, synthesiz...

Full description

Saved in:
Bibliographic Details
Published in:European journal of medicinal chemistry 2006-09, Vol.41 (9), p.1025-1040
Main Authors: Pallavicini, M, Fumagalli, L, Gobbi, M, Bolchi, C, Colleoni, S, Moroni, B, Pedretti, A, Rusconi, C, Vistoli, G, Valoti, E
Format: Article
Language:English
Subjects:
Adrenergic alpha-1 Receptor Antagonists
Adrenergic Antagonists - chemistry
Adrenergic Antagonists - pharmacology
Animals
CHO Cells
Cricetinae
Dioxanes - antagonists & inhibitors
Dioxanes - pharmacology
Humans
Methylamines - antagonists & inhibitors
Methylamines - pharmacology
Molecular Structure
Quantitative Structure-Activity Relationship
Stereoisomerism
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0223-5234