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

• Published in: Journal of medicinal chemistry 2003-05, Vol.46 (11), p.2169-2176
• Main Authors: Gentili, Francesco, Bousquet, Pascal, Brasili, Livio, Dontenwill, Monique, Feldman, Josiane, Ghelfi, Francesca, Giannella, Mario, Piergentili, Alessandro, Quaglia, Wilma, Pigini, Maria
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Biological and medical sciences; Blood Pressure - drug effects; Cardiovascular system; Heart Rate - drug effects; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Imidazoline Receptors; Kidney - metabolism; Male; Medical sciences; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; PC12 Cells; Pharmacology. Drug treatments; Rabbits; Radioligand Assay; Rats; Receptors, Drug - metabolism; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm021113r

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.