title: Synthesis and pharmacological evaluation of new biphenylic derivatives as CB2 receptor ligands.
abstract: Targeting type-2 cannabinoid receptor (CB2) is considered a feasible strategy to develop new drugs for the treatment of diseases like neuropathic pain, chronic inflammation, neurodegenerative disorders and cancer. Such drugs are devoid of the undesired central side effects that are typically mediated by the CB1 receptor. In this work we synthesized 18 biphenylic carboxamides as new CB2-selective ligands and evaluated their pharmacological profiles. The functional activity of these compounds is strongly influenced by the nature of the substituent at position 4' and 5 of the biphenyl scaffold. Position 5 seems to be responsible for the agonist or inverse agonist behaviour independently of the substituent in position 4', with the exception of the methoxyl group which transforms both full agonists and inverse agonists into neutral antagonists. This study provides a novel complete toolbox of CB2 functional modulators that derive from the same chemical scaffold. Such probes may be useful to investigate the biological role of CB2 receptors in cellular assays.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. Electronic address: simone.bertini@unipi.it.
authors.forename: Simone
authors.initials: S
authors.lastname: Bertini
authors.affiliation: Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research (NCCR) TransCure, University of Bern, Bühlstrasse 28, CH-3012 Bern, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Chicca
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy; Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research (NCCR) TransCure, University of Bern, Bühlstrasse 28, CH-3012 Bern, Switzerland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Arena
authors.affiliation: Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research (NCCR) TransCure, University of Bern, Bühlstrasse 28, CH-3012 Bern, Switzerland.
authors.forename: Stefano
authors.initials: S
authors.lastname: Chicca
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: Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research (NCCR) TransCure, University of Bern, Bühlstrasse 28, CH-3012 Bern, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
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: D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D016466:CHO Cells; D060326:Chemistry Techniques, Synthetic; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001713:Biphenyl Compounds; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C010574:biphenyl
keywords: Biphenyl-carboxamides; CB(2); CB(2) agonist; CB(2) antagonist; CB(2) inverse agonist; Cannabinoid receptor; Endocannabinoid system; Methylhonokiol