Please use this identifier to cite or link to this item: http://hdl.handle.net/10553/42992
Title: Synthesis, pharmacological evaluation and docking studies of pyrrole structure-based CB(2) receptor antagonists
Authors: Ragusa, Giulio
Gómez-Cañas, María
Morales, Paula
Hurst, Dow P.
Deligia, Francesco
Pazos, Ruth
Pinna, Gerard A.
Fernández-Ruiz, Javier
Goya, Pilar
Reggio, Patricia H.
Jagerovic, Nadine
García Arencibia, Moisés 
Murineddu, Gabriele
UNESCO Clasification: 32 Ciencias médicas
Keywords: Bioisosterism
Synthesis
Cannabinoid receptors
CB2
Antagonism, et al
Issue Date: 2015
Publisher: 0223-5234
Journal: European Journal of Medicinal Chemistry 
Abstract: 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]-GTPγS 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.
URI: http://hdl.handle.net/10553/42992
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2015.06.057
Source: European Journal Of Medicinal Chemistry[ISSN 0223-5234],v. 101, p. 651-667
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