Imidazoline Binding Sites (IBS) Profile Modulation: Key Role of the Bridge inDetermining I1-IBS or I2-IBS Selectivity within a Series of2-Phenoxymethylimidazoline Analogues
The α- and β-methyl derivatives of 2-phenylethylimidazoline (compounds 7 and 8) and thecorresponding enantiomers were prepared and tested with the purpose of studying the roleplayed by the ethylene bridge in modulating I1- and I2-IBS selectivity. The α-methylationappeared to be extremely critical regarding the affinity and selectivity for the I1-IBS subtypes(I1/I2 = 186 for imidazoline 7) and the stereospecificity of interaction (eudismic ratio (S)-(−)-7/(R)-(+)-7 = 5888). Instead, even if in a more limited fashion, the β-methylation tended towardI2-IBS selectivity (I2/I1 = 50 for imidazoline 8). The unsubstituted compound 4 (I2/I1 = 1479)proved to be considerably more potent and selective with respect to I2-IBS subtypes.
