RT Journal Article
T1 Tricyclic pyrazoles. Part 8. Synthesis, biological evaluation and modelling of tricyclic pyrazole carboxamides as potential CB2 receptor ligands with antagonist/inverse agonist properties
A1 Deiana, Valeria
A1 Gómez Cañas, María
A1 Pazos Rodríguez, María Ruth
A1 Fernández Ruiz, José Javier
A1 García Arencibia, Moisés
A1 Pinna, Gerard A.
AB 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.
PB Elsevier
SN 0223-5234
YR 2016
FD 2016-04
LK https://hdl.handle.net/20.500.14352/93744
UL https://hdl.handle.net/20.500.14352/93744
LA eng
NO Deiana V, Gómez-Cañas M, Pazos MR, Fernández-Ruiz  J, Asproni B, Cichero E, Fossa P, Muñoz  E, Deligia F, Murineddu G, García-Arencibia M, Pinna GA. Tricyclic pyrazoles. Part 8. Synthesis, biological evaluation and modelling of tricyclic pyrazolecarboxamides as potential CB2 receptor ligands with antagonist/inverse agonist properties.Eur J MedChem. 2016, 112:66-80.
DS Docta Complutense
RD 1 oct 2024