%0 Journal Article
%A Ragusa, Giulio
%A Gómez Cañas, María
%A Pazos Rodríguez, María Ruth
%A Fernández Ruiz, José Javier
%A García Arencibia, Moisés
%A Murineddu, Gabriele
%T Synthesis, pharmacological evaluation and docking studies of pyrrole structure-based CB 2 receptor antagonists
%D 2015
%@ 0223-5234
%U https://hdl.handle.net/20.500.14352/93748
%X During 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 CB2 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 (Ki in the low nM range) and selectivity for the CB2 receptor and both resulted to be antagonists/inverse agonists in [35S]-GTPgS binding analysis and in an in vitro CB2 receptor bioassay. Cannabinoid receptor binding data of the series allowed identifying steric constraints within the CB2 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 CB2 receptor inactive state model.
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