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Ragusa G.,University of Sassari | Gomez-Canas M.,Instituto Universitario Of Investigacion En Neuroquimica | Gomez-Canas M.,CIBER ISCIII | Gomez-Canas M.,Instituto Ramon Y Cajal Of Investigacion Sanitaria Irycis Madrid | And 18 more authors.
European Journal of Medicinal Chemistry | Year: 2015

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. © 2015 Elsevier Masson SAS. Source

Arce C.,Complutense University of Madrid | Arce C.,Instituto Universitario Of Investigacion En Neuroquimica | Diaz-Castroverde S.,Complutense University of Madrid | Canales M.J.,Instituto Universitario Of Investigacion En Neuroquimica | And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2012

The action of (Z)-N-(2-bromo-5-hydroxy-4-methoxybenzylidene)-2- methylpropan-2-amine oxide (RP6) on rat cortical neurons in culture, under oxygen-glucose-deprivation conditions, is reported. Cortical neurons in culture were treated during 1 h with OGD. After, they were placed under normal conditions during 24 h (reperfusion) in absence and presence of RP6. Different parameters were measured under each condition (control, 1 h OGD and 1 h OGD + reperfusion in absence and presence of RP6). RP6 protects neurons against ROS generation, lipid peroxidation levels, LDH release and mitochondrial membrane potential alteration, when administered during reperfusion after the OGD damage. Consequently, these results show that nitrone RP6 protects cells against ischemia injury produced during the reoxygenation, and could be a potential drug for the ictus therapy. © 2012 Elsevier Masson SAS. All rights reserved. Source

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