Structure-affinity studies for a novel series of homochiral naphtho and tetrahydronaphtho analogues of α 1 antagonist WB-4101

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 α _1a-AR with respect to the other two α ₁ subtypes and the 5-HT _1A receptor. The new compounds 2-8 and, in addition, the two enantiomers of 1 were tested in binding assays on the α _1a-AR, α _1b-AR, α _1d-AR, and the 5-HT _1A receptor. Two of them, namely the naphtho- and tetrahydronaphthodioxane derivatives (S)-2 and (S)-3, showed lower, but significantly more specific α _1a affinity than (S)-1, while the two enantiomers of the 2-methoxy-1-naphthoxy analogue 6 maintained most of the very high α _1a affinity of (S)-1 and its α _1a versus α _1b selectivity slightly increasing the α _1a/α _1d and α _1a/5HT _1A affinity ratios. The SAR data were evaluated in the light of known α ₁ subtype pharmacophores and of the α _1a-AR binding mode of WB-4101 resultant from literature mutagenesis studies disclosing some interesting consonances with these models.