Listing 1 - 1 of 1 |
Sort by
|
Choose an application
The endocannabinoid system constitutes an attractive target for pharmacotherapy. To date, two cannabinoid receptors have been identified, CB1 and CB2. The CB2 cannabinoid receptor is implicated in several physiological and pathological processes like peripheral pain, inflammation and cancer proliferation . In this work, we propose to evaluate the respective affinity for CB1 and CB2 receptors, as well as the functionality at CB2 receptor, of a set of derivatives which constitute potential novel cannabinoid ligands. These compounds are characterized by some important structural requirements exhibited by several cannabinoid reference ligands. The central pattern selected for the conception of these molecules is the 4- oxo-1,4-dihydroquinoline, a position isomer of the 2-quinolone of the JTE-907. From this model, two series of compounds have been evaluated, the 3-carboxamido-4-oxo-1,4- dihydroquinolines and derivatives including naphtyridines and cinnoline, and the 3-aroyl-4- oxo-1,4-dihydroquinolines. Several pharmacomodulations have been performed such as the incorporation of an hydrophilic or hydrophobie group in position 1, and an aromatic or hydrophobie group in position 3. The influence of the substitution of the quinolone by an halogen or the replacement of the oxygen by a sulfur in position 4 have also been determined. The results indicate that these compounds are selective for the CB2 receptor. The 3- carboxamido-4-oxo-1,4-dihydroquinoline derivatives containing an adamantyl group on the amide resulted in increased affinity compared to the aromatic analogues. Moreover, we determined that interactions with the CB2 receptor are stereoselective. Molecular modelisations suggested the existence of an hydrogen bond between the Ser193 and the oxygen of the carboxamide function. This was confirmed by the synthesis of amine derivatives showing highly decreased affinity, whereas retroamide derivatives, able to maintain this hydrogen bond, were unaffected. The majority of the molecules are agonists, however the substitution of the quinolone by a chlorine affected their functionality which tums to inverse agonists but only for compounds with an adamantyl on the amide function. Another structural modification that allows us to obtain an inverse agonist, without any changes in affinity, was the replacement of the oxygen by a sulphur in position 4. In position 1, benzyl substituents have been tested on the 3-carboxamido-4-oxo-1 ,4-dihydroquinolines and 3-aroyl-4-oxo-1,4- dihydroquinolines . The results indicated that an increased number of carbon atoms between the nitrogen and the benzyl differently influences the affinity according to the function and the substituents in position 3. Finally, we observed that the substitution of the phenyl by various halogens has an impact on the functionality of the ketonic serie. In conclusion, these structure-activity relationship studies allowed us to obtain selective and potent tools for the exploration of therapeutic potential of the CB² cannabinoid receptor.
Listing 1 - 1 of 1 |
Sort by
|