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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dc.contributor.authorDeiana, Valeria
dc.contributor.authorGómez Cañas, María
dc.contributor.authorPazos Rodríguez, María Ruth
dc.contributor.authorFernández Ruiz, José Javier
dc.contributor.authorGarcía Arencibia, Moisés
dc.contributor.authorPinna, Gerard A.
dc.date.accessioned2024-01-18T08:25:31Z
dc.date.available2024-01-18T08:25:31Z
dc.date.issued2016-04
dc.description.abstractPrevious 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.
dc.description.departmentDepto. de Bioquímica y Biología Molecular
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.statuspub
dc.identifier.citationDeiana 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.
dc.identifier.doi10.1016/j.ejmech.2016.02.005
dc.identifier.issn0223-5234
dc.identifier.officialurlhttps://www.sciencedirect.com/journal/european-journal-of-medicinal-chemistry
dc.identifier.relatedurlhttps://pubmed.ncbi.nlm.nih.gov/26890113/
dc.identifier.urihttps://hdl.handle.net/20.500.14352/93744
dc.journal.titleEuropean Journal of Medicinal Chemistry
dc.language.isoeng
dc.page.final80
dc.page.initial66
dc.publisherElsevier
dc.rights.accessRightsrestricted access
dc.subject.cdu577
dc.subject.keywordTricyclic pyrazoles
dc.subject.keywordSynthesis
dc.subject.keywordCannabinoid receptors
dc.subject.keywordCB2 antagonism
dc.subject.keywordMolecular modelling
dc.subject.ucmCiencias Biomédicas
dc.subject.unesco24 Ciencias de la Vida
dc.titleTricyclic pyrazoles. Part 8. Synthesis, biological evaluation and modelling of tricyclic pyrazole carboxamides as potential CB2 receptor ligands with antagonist/inverse agonist properties
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number112
dspace.entity.typePublication
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relation.isAuthorOfPublicationa397c938-999a-4def-a947-7f49b94dceb0
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relation.isAuthorOfPublication.latestForDiscovery4603fb50-fc50-4d17-a7fb-dc93ee96609c
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