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.
|Titolo:||Structure–affinity studies for a novel series of homochiral naphtho and tetrahydronaphtho analogues of α1 antagonist WB-4101|
|Autori interni:||PALLAVICINI, MARCO|
|Parole Chiave:||α 1-Adrenergic receptor subtypes; α 1-Antagonist; 5-HT 1A serotoninergic receptor; Binding affinity; WB-4101; WB-4101 analogues|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Data di pubblicazione:||2004|
|Digital Object Identifier (DOI):||10.1016/j.bmc.2004.06.040|
|Appare nelle tipologie:||01 - Articolo su periodico|