title: Might the observed α(2A)-adrenoreceptor agonism or antagonism of allyphenyline analogues be ascribed to different molecular conformations?
abstract: We recently reported that the α(2)-adrenoreceptor (AR) ligand allyphenyline (9) significantly enhanced morphine analgesia (due to its α(2C)-AR agonism), was devoid of sedative side effects (due to its α(2A)-AR antagonism), prevented and reversed morphine tolerance and dependence. To highlight the molecular characteristics compatible with this behaviour and to obtain novel agents potentially useful in chronic pain and opioid addiction management, the allyl group of 9 was replaced by substituents of moderate steric bulk (MR) and positive or negative lipophilic (π) and electronic (σ) contributions in all the possible combinations. Effective novel α(2C)-agonists/α(2A)-antagonists (2, 3, 10, 12, and 17) were obtained. This study also demonstrated that contradictory combinations of the physicochemical parameters were similarly able to induce the α(2A)-activation. Since we had previously observed that the absolute configuration affected only the potency, but not the functional profile of the ligands, we hypothesized that the α(2A)-activation was governed by a ligand preferred conformation. From a structural overlay investigation it emerged that an extended conformation appeared to be associated with dual α(2C)-agonism/α(2A)-antagonism, whereas a folded conformation associated with α(2C)-/α(2A)-agonism.
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università degli Studi di Camerino, via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Diamanti
authors.forename: Fabio
authors.initials: F
authors.lastname: Del Bello
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Carbonara
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrieri
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fracchiolla
authors.forename: Mario
authors.initials: M
authors.lastname: Giannella
authors.forename: Valerio
authors.initials: V
authors.lastname: Mammoli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piergentili
authors.forename: Katariina
authors.initials: K
authors.lastname: Pohjanoksa
authors.forename: Wilma
authors.initials: W
authors.lastname: Quaglia
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
authors.forename: Maria
authors.initials: M
authors.lastname: Pigini
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D000498:Allyl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D048288:Imidazolines / Q000737:chemistry* / Q000494:pharmacology*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*
chemical_list: C554422:2-(1-(2-allylphenoxy)ethyl)-4,5-dihydro-1H-imidazole; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000498:Allyl Compounds; D048288:Imidazolines; D018341:Receptors, Adrenergic, alpha-2