title: In vitro and in vivo pharmacological characterization of two novel selective cannabinoid CB(2) receptor inverse agonists.
abstract: We have previously developed quinolone-3-carboxamides with the aim of obtaining new ligands for both cannabinoid receptors, CB1 and CB2. Our preliminary screening led to the identification of cannabinoid receptor ligands characterized by high affinity and, in some cases, also selectivity for CB(2) receptors. Specifically, three compounds, 1, 2 and 3 showed high affinity for CB2 as well as high selectivity over CB1 receptors. In addition, the activity shown by 1 against the formalin-induced nocifensive response in mice, reported in our previous paper, suggests that quinolone-3-carboxamides possess anti-nociceptive properties. In the present work, we have performed functional in vitro bioassays with the aim of investigating the functional activity in the [35S]GTPgammaS binding assay of the other two compounds that, like 1, behave as CB2 selective ligands, and their potential analgesic actions in vivo. We found that both 2 and 3 behave in vitro as CB2 inverse agonists and are able to decrease nociceptive behaviour in the late phase of the formalin test only at the highest dose tested, although, at lower doses, they prevent the anti-nociceptive effects of a selective CB2 partial agonist in the formalin test. These results identify in 2 and 3 two novel, potent and selective CB2 antagonists/inverse agonists and confirm previous reports in the literature that, in addition to agonists at cannabinoid CB2 receptors, also inverse agonists/antagonists at these receptors show promise as anti-inflammatory agents.
authors: School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, UK.
authors: Maria Grazia
authors: MG
authors: Cascio
authors: Daniele
authors: D
authors: Bolognini
authors: Roger G
authors: RG
authors: Pertwee
authors: Enza
authors: E
authors: Palazzo
authors: Federico
authors: F
authors: Corelli
authors: Serena
authors: S
authors: Pasquini
authors: Vincenzo
authors: V
authors: Di Marzo
authors: Sabatino
authors: S
authors: Maione
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003511:Cyclohexanols / Q000494:pharmacology / Q000627:therapeutic use; D054314:Drug Inverse Agonism; D005557:Formaldehyde; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011869:Radioligand Assay; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D003511:Cyclohexanols; D015363:Quinolones; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D005557:Formaldehyde; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol