title: Alpha2-adrenoreceptors profile modulation and high antinociceptive activity of (S)-(-)-2-[1-(biphenyl-2-yloxy)ethyl]-4,5-dihydro-1H-imidazole.
abstract: A number of derivatives structurally related to cirazoline (1) were synthesized and studied with the purpose of modulating alpha2-adrenoreceptors selectivity versus both alpha1-adrenoreceptors and I2 imidazoline binding sites. The most potent alpha2-agonist was 2-[1-(biphenyl-2-yloxy)ethyl]-4,5-dihydro-1H-imidazole (7), whose key pharmacophoric features closely matched those found in the alpha2-agonist 2-(3-exo-(3-phenylprop-1-yl)-2-exo-norbornyl)amino-2-oxazoline (15). (S)-(-)-7 was the most potent of the two enantiomers, confirming the stereospecificity of the interaction with alpha2-adrenoreceptors. This eutomer was tested on two algesiometric paradigms and, because of the interaction with alpha2-adrenoreceptors, showed a potent and long-lasting antinociceptive activity, since it was abolished by the selective alpha2-antagonist RX821002.
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Gentili
authors.forename: Pascal
authors.initials: P
authors.lastname: Bousquet
authors.forename: Livio
authors.initials: L
authors.lastname: Brasili
authors.forename: Mariangela
authors.initials: M
authors.lastname: Caretto
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrieri
authors.forename: Monique
authors.initials: M
authors.lastname: Dontenwill
authors.forename: Mario
authors.initials: M
authors.lastname: Giannella
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.forename: Marina
authors.initials: M
authors.lastname: Perfumi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piergentili
authors.forename: Wilma
authors.initials: W
authors.lastname: Quaglia
authors.forename: Carla
authors.initials: C
authors.lastname: Rascente
authors.forename: Maria
authors.initials: M
authors.lastname: Pigini
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019329:Idazoxan / Q000031:analogs & derivatives / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D054755:Imidazoline Receptors; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D011955:Receptors, Drug / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: C444320:2-(1-(biphenyl-2-yloxy)ethyl)-4,5-dihydro-1H-imidazole; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D001713:Biphenyl Compounds; D007093:Imidazoles; D054755:Imidazoline Receptors; D018341:Receptors, Adrenergic, alpha-2; D011955:Receptors, Drug; C058525:2-methoxyidazoxan; D019329:Idazoxan