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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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