title: Separation of alpha-adrenergic and imidazoline/guanidinium receptive sites (IGRS) activity in a series of imidazoline analogues of cirazoline.
abstract: To characterize the structure-activity relationship between alpha 1-adrenergic receptors and the family of imidazoline/guanidinium receptive sites (IGRS), we synthesized and characterized a series of analogues of cirazoline, an imidazoline with high affinity for alpha 1-adrenergic receptors and IGRS. Analysis of potency, affinity and efficacy of the synthesized molecules indicate different structure-activity relationships for IGRS and alpha-adrenergic receptors. Cirazoline exhibits a 25-fold higher affinity for IGRS (pKi 7.9) than for alpha 1-adrenergic receptors. Replacement of the cyclopropyl ring with an isopropoxy group resulted in a molecule that was 20-fold more selective for alpha 1-adrenergic receptors than for IGRS, i.e. a 500-fold increase in selectivity relative to cirazoline. The unsubstituted derivative 3 and the methyl and allyl substituted analogues 4 and 12 are of particular interest: compounds 3 and 4 recognize IGRS with high affinity (pKi 7.83 and 8.17) and high selectivity (398 and 123) with respect to the alpha 1-adrenergic receptor; compound 12 also recognizes IGRS with high affinity (pKi 8.08) and high selectivity (228 and 138) with respect to the alpha 2B and alpha 2C-adrenergic receptor subtypes. Thanks to their IGRS selectivity, these compounds represent novel and valuable pharmacological tools for the characterization and elucidation of the physiological role of these novel sites.
authors.affiliation: Dípartimento di Scienze Farmaceutiche, Università di Modena, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Brasili
authors.forename: M
authors.initials: M
authors.lastname: Pigini
authors.forename: G
authors.initials: G
authors.lastname: Marucci
authors.forename: W
authors.initials: W
authors.lastname: Quaglia
authors.forename: L
authors.initials: L
authors.lastname: Malmusi
authors.forename: S M
authors.initials: SM
authors.lastname: Lanier
authors.forename: B
authors.initials: B
authors.lastname: Lanier
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D007093:Imidazoles / Q000494:pharmacology*; D054755:Imidazoline Receptors; D066298:In Vitro Techniques; D008297:Male; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D011955:Receptors, Drug / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D054755:Imidazoline Receptors; D011942:Receptors, Adrenergic, alpha; D011955:Receptors, Drug; C014282:cirazoline