%0 Journal Article
%A Deiana, Valeria
%A Gómez Cañas, María
%A Pazos Rodríguez, María Ruth
%A Fernández Ruiz, José Javier
%A García Arencibia, Moisés
%A Pinna, Gerard A.
%T Tricyclic pyrazoles. Part 8. Synthesis, biological evaluation and modelling of tricyclic pyrazole carboxamides as potential CB2 receptor ligands with antagonist/inverse agonist properties
%D 2016
%@ 0223-5234
%U https://hdl.handle.net/20.500.14352/93744
%X Previous studies have investigated the relevance and structure-activity relationships (SARs) of pyrazolederivatives in relation with cannabinoid receptors, and the series of tricyclic 1,4-dihydroindeno[1,2-c]pyrazoles emerged as potent CB2 receptor ligands. In the present study, novel 1,4-dihydroindeno[1,2-c]pyrazole and 1H-benzo[g]indazole carboxamides containing a cyclopropyl or a cyclohexyl substituentwere designed and synthesized to evaluate the influence of these structural modifications towards CB1and CB2 receptor affinities. Among these derivatives, compound 15 (6-cyclopropyl-1-(2,4-dichlorophenyl)-N-(adamantan-1-yl)-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide) showed thehighest CB2 receptor affinity (Ki ¼ 4 nM) and remarkable selectivity (KiCB1/KiCB2 ¼ 2232), whereas asimilar affinity, within the nM range, was seen for the fenchyl derivative (compound 10: Ki ¼ 6 nM), forthe bornyl analogue (compound 14: Ki ¼ 38 nM) and, to a lesser extent, for the aminopiperidine de rivative (compound 6: Ki ¼ 69 nM). Compounds 10 and 14 were also highly selective for the CB2 receptor(KiCB1/KiCB2 > 1000), whereas compound 6 was relatively selective (KiCB1/KiCB2 ¼ 27). The four com pounds were also subjected to GTPgS binding analysis showing antagonist/inverse agonist properties(IC50 for compound 14 ¼ 27 nM, for 15 ¼ 51 nM, for 10 ¼ 80 nM and for 6 ¼ 294 nM), and this activitywas confirmed for the three more active compounds in a CB2 receptor-specific in vitro bioassay con sisting in the quantification of prostaglandin E2 release by LPS-stimulated BV2 cells, in the presence andabsence of WIN55,212-2 and/or the investigated compounds. Modelling studies were also conducted with the four compounds, which conformed with the structural requirements stated for the binding ofantagonist compounds to the human CB2 receptor.
%~