Imidazoline Binding Sites (IBS) Profile Modulation: Key Role of the Bridge in Determining I1-IBS or I2-IBS Selectivity within a Series of 2-Phenoxymethylimidazoline Analogues

Abstract

The α- and β-methyl derivatives of 2-phenylethylimidazoline (compounds 7 and 8) and the corresponding enantiomers were prepared and tested with the purpose of studying the role played by the ethylene bridge in modulating I₁- and I₂-IBS selectivity. The α-methylation appeared 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 toward I₂-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.