Tricyclic pyrazoles. Part 8. Synthesis, biological evaluation and modelling of tricyclic pyrazole carboxamides as potential CB2 receptor ligands with antagonist/inverse agonist properties
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2016
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Elsevier
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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.
Abstract
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.