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Eur J Med Chem. 2016 Apr 13;112:66-80. doi: 10.1016/j.ejmech.2016.02.005. Epub 2016 Feb 6.

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

Author information

1
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy.
2
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain; Campus de Excelencia Internacional (CEI-Moncloa), Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
3
Dipartmento di Farmacia, Sezione Chimica del Farmaco e del Prodotto Cosmetico, Università degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
4
Maimonides Biomedical Research Institute of Córdoba, Reina Sofía University Hospital, Dept of Cell Biology, Physiology and Immunology, University of Córdoba, Avda Menéndez Pidal s/n, 14004 Córdoba, Spain.
5
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy. Electronic address: muri@uniss.it.
6
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain; Campus de Excelencia Internacional (CEI-Moncloa), Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; Grupo de Investigación en Medio Ambiente y Salud, Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Spain.

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 = 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.

KEYWORDS:

CB(2) antagonism; Cannabinoid receptors; Molecular modelling; Synthesis; Tricyclic pyrazoles

PMID:
26890113
DOI:
10.1016/j.ejmech.2016.02.005
[Indexed for MEDLINE]

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