title: Favourable involvement of α2A-adrenoreceptor antagonism in the I₂-imidazoline binding sites-mediated morphine analgesia enhancement.
abstract: Aim of the present study was to obtain novel α(2)-adrenoreceptor (α(2)-AR) antagonists, possibly endowed with subtype-selectivity. Therefore, inspired by the non subtype-selective α(2)-AR antagonist idazoxan, we designed 1,4-dioxane derivatives bearing an aromatic area in position 5 or 6 and the imidazoline nucleus in position 2. Among the novel molecules 1-6, compound 2, with a trans stereochemical relationship between 5-phenyl and 2-imidazoline groups, was able to antagonize the sole α(2A)-subtype. Moreover, 2 showed an affinity at I(2)-imidazoline binding sites (I(2)-IBS) comparable to that at α(2A)-AR. In in vivo studies 2 strongly increased morphine analgesia. This interesting behaviour appeared to be induced by the favourable involvement of α(2A)-AR antagonism in the I(2)-IBS-mediated morphine analgesia enhancement.
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Mammoli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bonifazi
authors.forename: Fabio
authors.initials: F
authors.lastname: Del Bello
authors.forename: Eleonora
authors.initials: E
authors.lastname: Diamanti
authors.forename: Mario
authors.initials: M
authors.lastname: Giannella
authors.forename: Alan L
authors.initials: AL
authors.lastname: Hudson
authors.forename: Laura
authors.initials: L
authors.lastname: Mattioli
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: Federica
authors.initials: F
authors.lastname: Titomanlio
authors.forename: Maria
authors.initials: M
authors.lastname: Pigini
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D006801:Humans; D019329:Idazoxan / Q000737:chemistry; D048288:Imidazolines / Q000737:chemistry*; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D048288:Imidazolines; D018341:Receptors, Adrenergic, alpha-2; D009020:Morphine; D019329:Idazoxan