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 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 -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.
Gentili
Francesco
F
Dipartimento di Scienze Chimiche, Università degli Studi di Camerino, via S. Agostino 1, 62032 Camerino, Italy.
Bousquet
Pascal
P
Brasili
Livio
L
Dontenwill
Monique
M
Feldman
Josiane
J
Ghelfi
Francesca
F
Giannella
Mario
M
Piergentili
Alessandro
A
Quaglia
Wilma
W
Pigini
Maria
M
D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054755:Imidazoline Receptors; D007668:Kidney / Q000378:metabolism; D008297:Male; D016716:PC12 Cells; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D011955:Receptors, Drug / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C474825:2-(1-methyl-2-phenylethyl)-4,5-dihydro-1H-imidazole; D007093:Imidazoles; D054755:Imidazoline Receptors; D011955:Receptors, Drug; C410887:imidazoline I1 receptors