Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/5501
Title: Synthesis, Cannabinoid Receptor Affinity, and Molecular Modeling Studies of Substituted 1-Aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides.
Authors: R., Silvestri
M. G., Cascio
G., LA REGINA
G., Piscitelli
G., Lavecchia
Brizzi, Antonella 
Pasquini, Serena
Botta, Maurizio 
E., Novellino
V., DI MARZO
Corelli, Federico 
Issue Date: 2008
Project: None 
Journal: JOURNAL OF MEDICINAL CHEMISTRY
Abstract: 
The new 1-phenyl-5-(1 H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compounds AM251 and SR144528 for cannabinoid hCB 1 and hCB 2 receptor affinity. Compounds bearing 2,4-dichlorophenyl or 2,4-difluorophenyl groups at position 1 and 2,5-dimethylpyrrole moiety at position 5 of the pyrazole nucleus were generally more selective for hCB 1. On the other hand, the N-cyclohexyl group at the 3-carboxamide was the determinant for the hCB 2 selectivity, in particular when a 3,4-dichlorophenyl group was also present at position 1. Compound 26 was the most selective ligand for the hCB 1 receptor ( K i (CB 2)/ K i (CB 1) = 140.7). Derivative 30, the most potent hCB 1 ligand ( K i = 5.6 nM), was equipotent to AM251 and behaved as an inverse agonist in the cAMP assay (EC 50 approximately 1 nM). The carbonyl oxygen of both 26 and 30 formed a H-bond with K3.28(192), while the substituents at the nitrogen fitted in a pocket formed by lipophilic residues. This H-bonding interaction was proposed to account for the high affinity for receptors' inactive state and the inverse agonist activity.
Description: 
35695
URI: http://hdl.handle.net/20.500.12779/5501
ISSN: 0022-2623
DOI: 10.1021/jm070566z
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