title: Synthesis, biological activity and molecular modeling of new biphenylic carboxamides as potent and selective CB2 receptor ligands.
abstract: The CB2 receptor is a therapeutic target of increasing importance for several diseases, including pain, inflammation, neurodegeneration, cancer and osteoporosis. While several compounds showing CB2-selective agonist or inverse agonist properties have been developed, only few CB2 receptor selective neutral antagonists are actually known. Such type of compounds could be useful to study more in depth the role of the CB2 receptor, because they lack the ability to counteract its "constitutive" activity. Here we describe the synthesis and biological activity of a series of biphenylic carboxamides as a new class of CB2 receptor selective ligands. In binding assays, one of these compounds showed good CB2 receptor affinity and selectivity (Ki = 11.48 nM; Selectivity Index = 130). Furthermore, in functional assays, the same compound showed a very interesting pharmacological profile as CB2 receptor selective neutral antagonist. These results pave the way to further developments, including structural optimization, with the aim to obtain more potent CB2 receptor ligands with this peculiar feature.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. Electronic address: simone.bertini@farm.unipi.it.
authors.forename: Simone
authors.initials: S
authors.lastname: Bertini
authors.affiliation: University of Eastern Finland, Faculty of Health Sciences, School of Pharmacy, PO Box 1627, 70211 Kuopio, Finland; University of Eastern Finland, Faculty of Health Sciences, Institute of Biomedicine, School of Medicine, PO Box 1627, 70211 Kuopio, Finland.
authors.forename: Teija
authors.initials: T
authors.lastname: Parkkari
authors.affiliation: University of Eastern Finland, Faculty of Health Sciences, Institute of Biomedicine, School of Medicine, PO Box 1627, 70211 Kuopio, Finland.
authors.forename: Juha R
authors.initials: JR
authors.lastname: Savinainen
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Arena
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saccomanni
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Saguto
authors.affiliation: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.affiliation: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Allarà
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Bruno
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.affiliation: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Clementina
authors.initials: C
authors.lastname: Manera
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001713:Biphenyl Compounds; D008024:Ligands; D043885:Receptor, Cannabinoid, CB2
keywords: Biphenylic carboxamides; CB2 receptor; CB2 receptor neutral antagonist; Cannabinoid