title: CB2-selective cannabinoid receptor ligands: synthesis, pharmacological evaluation, and molecular modeling investigation of 1,8-Naphthyridin-2(1H)-one-3-carboxamides.
abstract: We have recently identified 1,8-naphthyridin-2(1H)-one-3-carboxamide as a new scaffold very suitable for the development of new CB2 receptor potent and selective ligands. In this paper we describe a number of additional derivatives in which the same central scaffold has been variously functionalized in position 1 or 6. All new compounds showed high selectivity and affinity in the nanomolar range for the CB2 receptor. Furthermore, we found that their functional activity is controlled by the presence of the substituents at position C-6 of the naphthyridine scaffold. In fact, the introduction of substituents in this position determined a functionality switch from agonist to antagonists/inverse agonists. Finally, docking studies showed that the difference between the pharmacology of these ligands may be in the ability/inability to block the Toggle Switch W6.48(258) (χ1 g+ → trans) transition.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Lucchesi
authors.forename: Dow P
authors.initials: DP
authors.lastname: Hurst
authors.forename: Derek M
authors.initials: DM
authors.lastname: Shore
authors.forename: Simone
authors.initials: S
authors.lastname: Bertini
authors.forename: Brandie M
authors.initials: BM
authors.lastname: Ehrmann
authors.forename: Marco
authors.initials: M
authors.lastname: Allarà
authors.forename: Lyle
authors.initials: L
authors.lastname: Lawrence
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saccomanni
authors.forename: Haleli
authors.initials: H
authors.lastname: Sharir
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Mary E
authors.initials: ME
authors.lastname: Abood
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Reggio
authors.forename: Clementina
authors.initials: C
authors.lastname: Manera
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: C574518:1,8-naphthyridin-2(1H)-one; D008024:Ligands; D009287:Naphthyridines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2