Within our studies on structure activity relationships of 4-quinolone-3-carboxamides as cannabinoid ligands, a new series of compounds characterized by a fluoro or phenylthio group at 7-position and different substituents at N1 and carboxamide nitrogen were synthesized and evaluated for their binding ability to cannabinoid type 1 (CBI) and type 2 (CB2) receptors. Most of the compounds showed affinity for one or both cannabinoid receptors at nanomolar concentration, with K-i(CB1) and K-i(CB2) values ranging 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 CBI receptor. Compounds 4 and 40, a CB2 and a CBI ligand, respectively, behaved as partial agonists in the [S-35]GTP gamma S 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 unable to cross the blood brain barrier. (C) 2012 Elsevier Masson SAS. All rights reserved.
Authors wish to thank Dr. Elisa Turlizzi (Siena Biotech SpA, Siena, Italy) for helpful discussions and Mr Marco Allarà (CNR, Pozzuoli) and Mrs Lesley A. Stevenson (University of Aberdeen) for
- Cannabinoid ligands
- Partial agonists
- Peripheral ligands
- SELECTIVE ANTAGONIST