A number of enantiomeric pairs of naphthodioxane, tetrahydronaphthodioxane and naphthoxy analogues of WB-4101 (1) were designed and synthesized in order to improve the selectivity profile of the parent compound, hopefully in favour of the α1a -AR with respect to the other two α1 subtypes and the 5-HT1A receptor. The new compounds 2 –8 and, in addition, the two enantiomers of 1 were tested in binding assays on the α1a -AR, α1b -AR, α1d -AR, and the 5-HT1A receptor. Two of them, namely the naphtho- and tetrahydronaphthodioxane derivatives (S)-2 and (S)-3, showed lower, but significantly more specific α1a affinity than (S)-1, while the two enantiomers of the 2-methoxy-1-naphthoxy analogue 6 maintained most of the very high α1a affinity of (S)-1 and its α1a versus α1b selectivity slightly increasing the α1a /α1d and α1a /5HT1A affinity ratios. The SAR data were evaluated in the light of known α1 subtype pharmacophores and of the α1a -AR binding mode of WB-4101 resultant from literature mutagenesis studies disclosing some interesting consonances with these models.

Structure–affinity studies for a novel series of homochiral naphtho and tetrahydronaphtho analogues of α1 antagonist WB-4101 / C. Bolchi, P. Catalano, L. Fumagalli, M. Gobbi, M. Pallavicini, A. Pedretti, L. Villa, G. Vistoli, E. Valoti. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 12:18(2004), pp. 4937-4951. [10.1016/j.bmc.2004.06.040]

Structure–affinity studies for a novel series of homochiral naphtho and tetrahydronaphtho analogues of α1 antagonist WB-4101

C. Bolchi;L. Fumagalli;M. Pallavicini;A. Pedretti;L. Villa;G. Vistoli;E. Valoti
2004

Abstract

A number of enantiomeric pairs of naphthodioxane, tetrahydronaphthodioxane and naphthoxy analogues of WB-4101 (1) were designed and synthesized in order to improve the selectivity profile of the parent compound, hopefully in favour of the α1a -AR with respect to the other two α1 subtypes and the 5-HT1A receptor. The new compounds 2 –8 and, in addition, the two enantiomers of 1 were tested in binding assays on the α1a -AR, α1b -AR, α1d -AR, and the 5-HT1A receptor. Two of them, namely the naphtho- and tetrahydronaphthodioxane derivatives (S)-2 and (S)-3, showed lower, but significantly more specific α1a affinity than (S)-1, while the two enantiomers of the 2-methoxy-1-naphthoxy analogue 6 maintained most of the very high α1a affinity of (S)-1 and its α1a versus α1b selectivity slightly increasing the α1a /α1d and α1a /5HT1A affinity ratios. The SAR data were evaluated in the light of known α1 subtype pharmacophores and of the α1a -AR binding mode of WB-4101 resultant from literature mutagenesis studies disclosing some interesting consonances with these models.
α 1-Adrenergic receptor subtypes; α 1-Antagonist; 5-HT 1A serotoninergic receptor; Binding affinity; WB-4101; WB-4101 analogues
Settore CHIM/08 - Chimica Farmaceutica
2004
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/7244
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