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

The alpha- and beta-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 alpha-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 beta-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.