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 CB2receptor 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 CB1and CB2receptor 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 CB2receptor affinity (Ki= 4 nM) and remarkable selectivity (KiCB1/KiCB2= 2232), whereas a similar affinity, within the nM range, was seen for the fenchyl derivative (compound 10: Ki= 6 nM), for the bornyl analogue (compound 14: Ki= 38 nM) and, to a lesser extent, for the aminopiperidine derivative (compound 6: Ki= 69 nM). Compounds 10 and 14 were also highly selective for the CB2receptor (KiCB1/KiCB2> 1000), whereas compound 6 was relatively selective (KiCB1/KiCB2= 27). The four compounds were also subjected to GTPγS binding analysis showing antagonist/inverse agonist properties (IC50for compound 14 = 27 nM, for 15 = 51 nM, for 10 = 80 nM and for 6 = 294 nM), and this activity was confirmed for the three more active compounds in a CB2receptor-specific in vitro bioassay consisting 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 CB2receptor.
Tricyclic Pyrazoles. Part 8. Synthesis, Biological Evaluation and Modelling of Tricyclic Pyrazole Carboxamides as Potential CB2 Receptor Ligands with Antagonist/Inverse Agonist Properties / Deiana, V; Gómez Cañas, M; Pazos, M. R.; Fernández Ruiz, J; Asproni, B; Cichero, E; Fossa, P; Muñoz, E; Deligia, F; Murineddu, Gabriele; García Arencibia, M; Pinna, Gerard Aime. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 112:(2016), pp. 66-80. [10.1016/j.ejmech.2016.02.005]
Tricyclic Pyrazoles. Part 8. Synthesis, Biological Evaluation and Modelling of Tricyclic Pyrazole Carboxamides as Potential CB2 Receptor Ligands with Antagonist/Inverse Agonist Properties.
Asproni B;MURINEDDU, Gabriele;PINNA, Gerard Aime
2016-01-01
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 CB2receptor 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 CB1and CB2receptor 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 CB2receptor affinity (Ki= 4 nM) and remarkable selectivity (KiCB1/KiCB2= 2232), whereas a similar affinity, within the nM range, was seen for the fenchyl derivative (compound 10: Ki= 6 nM), for the bornyl analogue (compound 14: Ki= 38 nM) and, to a lesser extent, for the aminopiperidine derivative (compound 6: Ki= 69 nM). Compounds 10 and 14 were also highly selective for the CB2receptor (KiCB1/KiCB2> 1000), whereas compound 6 was relatively selective (KiCB1/KiCB2= 27). The four compounds were also subjected to GTPγS binding analysis showing antagonist/inverse agonist properties (IC50for compound 14 = 27 nM, for 15 = 51 nM, for 10 = 80 nM and for 6 = 294 nM), and this activity was confirmed for the three more active compounds in a CB2receptor-specific in vitro bioassay consisting 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 CB2receptor.File | Dimensione | Formato | |
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