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|Title:||Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 6. Synthesis and Pharmacological Evaluation of 7-Substituted 4-Quinolone-3-carboxamide Derivatives as High Affinity Ligands for Cannabinoid Receptors||Authors:||Pasquini, Serena
DE ROSA, Maria
Caradonna, N. P.
Cascio, M. G.
Pertwee, R. G.
Di Marzo, V.
|Issue Date:||2012||Project:||None||Journal:||EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY||Abstract:||
Within our studies on structureeactivity relationships of 4-quinolone-3-carboxamides as cannabinoidligands, a new series of compounds characterized by a fluoro or phenylthio group at 7-position anddifferent substituents at N1 and carboxamide nitrogen were synthesized and evaluated for their bindingability to cannabinoid type 1 (CB1) and type 2 (CB2) receptors. Most of the compounds showed affinityfor one or both cannabinoid receptors at nanomolar concentration, with Ki(CB1) and Ki(CB2) valuesranging from 2.45 to >10,000 nM and from 0.09 to 957 nM, respectively. The N-(3,4-dichlorobenzyl)amide derivatives 27 and 40 displayed relatively low affinity, but high selectivity towards the CB1receptor. Compounds 4 and 40, a CB2 and a CB1 ligand, respectively, behaved as partial agonists in the[35S]GTPgS assay. They showed very low permeability through (MDCK-MDR1) cells and might, therefore,represent possible lead structures for further optimization in the search for cannabinoid ligands unableto cross the bloodebrain barrier
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