Academic Journal
Tricyclic pyrazoles. Part 8. Synthesis, biological evaluation and modelling of tricyclic pyrazole carboxamides as potential CB 2 receptor ligands with antagonist/inverse agonist properties
| العنوان: | Tricyclic pyrazoles. Part 8. Synthesis, biological evaluation and modelling of tricyclic pyrazole carboxamides as potential CB 2 receptor ligands with antagonist/inverse agonist properties |
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| المؤلفون: | Deiana, Valeria, Gómez-Cañas, María, Pazos, M. Ruth, Fernández-Ruiz, Javier, Asproni, Battistina, Cichero, Elena, Fossa, Paola, Muñoz, Eduardo, Deligia, Francesco, Murineddu, Gabriele, García-Arencibia, Moisés, Pinna, Gerard A. |
| المساهمون: | 57194483512, 47761206700, 6701326923, 7006533053, 7801341853, 23970379500, 7004138079, 7202348306, 55241643800, 6603506924, 15821889300, 35546140700, 3479936, 2056921, 1182976, 180726, 1475866, 749265, 31927177, 76495, 5628976, 974941, 1760567, 267952, WOS:Deiana, V, WOS:Gomez-Canas, M, WOS:Pazos, MR, WOS:Fernandez-Ruiz, J, WOS:Asproni, B, WOS:Cichero, E, WOS:Fossa, P, WOS:Munoz, E, WOS:Deligia, F, WOS:Murineddu, G, WOS:Garcia-Arencibia, M, WOS:Pinna, GA |
| المصدر: | European Journal of Medicinal Chemistry [ISSN 0223-5234], v. 112, p. 66-80 |
| بيانات النشر: | 0223-5234 |
| سنة النشر: | 2016 |
| المجموعة: | Universidad de Las Palmas de Gran Canaria: Acceda |
| مصطلحات موضوعية: | 32 Ciencias médicas, CB(2) antagonism, Cannabinoid receptors, Molecular modelling, Synthesis, Tricyclic pyrazoles |
| الوصف: | 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 = 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 CB2 receptor (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 (IC50 for 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 CB2 receptor-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 CB2 receptor. ; 80 ; 66 ; 1,272 ; 4,519 ; Q1 ; Q1 ; SCIE |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0223-5234 |
| Relation: | European Journal of Medicinal Chemistry; 112; http://hdl.handle.net/10553/42990; 2-s2.0-84981298101; 000372558200007; Sí |
| DOI: | 10.1016/j.ejmech.2016.02.005 |
| الاتاحة: | http://hdl.handle.net/10553/42990 https://doi.org/10.1016/j.ejmech.2016.02.005 |
| رقم الانضمام: | edsbas.C02CB7DA |
| قاعدة البيانات: | BASE |
| تدمد: | 02235234 |
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| DOI: | 10.1016/j.ejmech.2016.02.005 |