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
AB Previous studies have investigated the relevance and structure-activity relationships (SARs) of pyrazole derivatives 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 substituent were designed and synthesized to evaluate the influence of these structural modifications towards CB1 and 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 the highest CB2 receptor affinity (Ki ¼ 4 nM) and remarkable selectivity (KiCB1/KiCB2 ¼ 2232), whereas a similar affinity, within the nM range, was seen for the fenchyl derivative (compound 10: Ki ¼ 6 nM), for the 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 activity was 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 and absence 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 of antagonist compounds to the human CB2 receptor.
PB Elsevier
SN 0223-5234
YR 2016
FD 2016
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.
NO Regione Autonoma della Sardegna (Italia)
NO Comunidad de Madrid
NO Ministerio de Economía y Competitividad (España)
DS Docta Complutense
RD 6 abr 2025