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 I-1- and I-2-IBS selectivity. The alpha-methylation appeared to be extremely critical regarding the affinity and selectivity for the I-1-IBS subtypes (I-1/I-2 = 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 P-methylation tended toward I-2-IBS selectivity (I2I1 = 50 for imidazoline 8). The unsubstituted compound 4 (I-2/I-1 = 1479) proved to be considerably more potent and selective with respect to I-2-IBS subtypes.