TY - JOUR
T1 - QSAR study for a novel series of ortho disubstituted phenoxy analogues of α1-adrenoceptor antagonist WB4101
AU - Pallavicini, M.
AU - Fumagalli, L.
AU - Gobbi, M.
AU - Bolchi, C.
AU - Colleoni, S.
AU - Moroni, B.
AU - Pedretti, A.
AU - Rusconi, C.
AU - Vistoli, G.
AU - Valoti, E.
PY - 2006/9
Y1 - 2006/9
N2 - On the basis of the affinities at the α1a-, α1b- and α1d-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 α1 antagonist WB4101, and of the ortho monosubstituted derivatives, suggesting some distinctive aspects of the interaction of the phenoxy moiety, in particular with the α1a-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 α1a 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.
AB - On the basis of the affinities at the α1a-, α1b- and α1d-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 α1 antagonist WB4101, and of the ortho monosubstituted derivatives, suggesting some distinctive aspects of the interaction of the phenoxy moiety, in particular with the α1a-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 α1a 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.
KW - α-Adrenoreceptor
KW - 5-HT receptor
KW - Binding affinity
KW - QSAR
KW - WB4101 analogues
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U2 - 10.1016/j.ejmech.2006.04.004
DO - 10.1016/j.ejmech.2006.04.004
M3 - Article
C2 - 16737760
AN - SCOPUS:33748441537
VL - 41
SP - 1025
EP - 1040
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
IS - 9
ER -