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Title

Synthesis, pharmacological evaluation and docking studies of pyrrole structure-based CB<inf>2</inf> receptor antagonists

AuthorsRagusa, Giulio; Gómez-Cañas, María; Morales, Paula ; Hurst, D. P.; Deligia, F.; Pazos, Ruth; Pinna, Gerard A.; Fernández-Ruiz, Javier; Goya, Pilar ; Reggio, Patricia; Jagerovic, Nadine ; García-Arencibia, M.; Murineddu, Gabriele
Issue Date2015
PublisherElsevier
CitationEuropean Journal of Medicinal Chemistry 101: 651-667 (2015)
AbstractDuring the last years, there has been a continuous interest in the development of cannabinoid receptor ligands that may serve as therapeutic agents and/or as experimental tools. This prompted us to design and synthesize analogues of the CB<inf>2</inf> receptor antagonist N-fenchyl-5-(4-chloro-3-methyl-phenyl)-1-(4-methyl-benzyl)-1H-pyrazole-3-carboxamide (SR144528). The structural modifications involved the bioisosteric replacement of the pyrazole ring by a pyrrole ring and variations on the amine carbamoyl substituents. Two of these compounds, the fenchyl pyrrole analogue 6 and the myrtanyl derivative 10, showed high affinity (K<inf>i</inf> in the low nM range) and selectivity for the CB<inf>2</inf> receptor and both resulted to be antagonists/inverse agonists in [<sup>35</sup>S]-GTPγS binding analysis and in an in vitro CB<inf>2</inf> receptor bioassay. Cannabinoid receptor binding data of the series allowed identifying steric constraints within the CB<inf>2</inf> binding pocket using a study of Van der Waals' volume maps. Glide docking studies revealed that all docked compounds bind in the same region of the CB<inf>2</inf> receptor inactive state model.
Publisher version (URL)http://dx.doi.org/10.1016/j.ejmech.2015.06.057
URIhttp://hdl.handle.net/10261/126319
DOI10.1016/j.ejmech.2015.06.057
Identifiersdoi: 10.1016/j.ejmech.2015.06.057
issn: 1768-3254
e-issn: 1768-3254
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