Design, Syntheses And Biological Evaluations Of Triazolones, Coumarins, And Quinolinediones As Novel Selective Ligands For The Cannabinoid CB2Receptor

The endocannabinoid system plays a major role in various physiological and pathological processes, which provides an attractive target for drug development. The cannabinoid CB2receptor represents as a promising drug target for the treatment of pain, atopic disorders, osteoporosis, neurodegenerative diseases, etc., without serious CNS side effects. Consequently, the discovery and structural optimization of selective ligands for the CB2receptor has attracted considerable attention in recent years.On the basis of the lead diarylpyrazole derivatives and the reported CoMFA model, a set of1,2,4-triazolone analogs was designed using a combined approach of scaffold hopping and pharmacophore-oriented method. The target compounds were synthesized with different substituents at the N1, C3, and N4positions of the new scaffold. These compounds exhibited modest in vitro antagonistic activities on the cannabinoid receptors, but low selectivities for the CB2receptor. In addition, the N4-substituted group of a ligand played a pivotal role in regulating the selectivity. Furthermore, homology models of both CB1and CB2receptors were built up according to the X-ray structure of human β2-adrenoreceptor and optimized in an aqueous membrane system by MD simulations. The binding modes of1,2,4-triazolone analogs with the cannabinoid receptor homology models were analyzed to calculate the structural requirements for improving the bioactivity and selectivity of a ligand for the cannabinoid receptors.In the second part of the thesis, guided by the CoMFA model of the lead2-quinolone and2-pyridone analogs, a novel series of coumarin derivatives was designed by combining the structural features of some known cannabinoid ligands. Herein, a family of37molecules was synthesized and biologically evaluated by calcium mobilization assays. The related compounds were potent and selective ligands for the CB2receptor and some displayed higher in vitro bioactivities than the reference compounds. The SAR studies indicated a straight chain at C8position and an aliphatic group of the amide group would be favorable to the CB2receptor bioactivity of a ligand. Furthermore, the functionality of a ligand was controlled by the substituent on the coumarin scaffold. In addition, flexible docking simulations were carried out to calculate the receptor-ligand interactions, which implied the W258(6.48)/F117(3.36) motif of the CB2receptor would be the key residues for mediating the functional activity.Subsequently, a collection of quinoline-2,4(1H,3H)-dione derivatives was designed by combining the privileged quinolone scaffolds, and systematically structural modification was performed to investigate the effects of various substituted decorations of the nucleus on the CB2receptor activity. Most of these compounds exhibited excellent in vitro bioactivities and selectivities for the CB2receptor. Hereinto, the best agonistic ligand3-140(CB2EC50=0.019μM) and antagonistic compound3-158(CB2IC50=0.007μM) displayed23-and92-fold higher bioactivities in comparison to the corresponding reference compounds under the same assay condition, respectively. Furthermore, the administration of archetypical compound3-115could dose-dependently alleviate the clinical signs of mice EAE model and reduce CNS leukocyte infiltration and demyelination. The results indicated the quinolone-2,4(1#,3#)-dione derivatives would be potential leads for the drug development of multiple sclerosis. In addition, the molecular docking simulations and CoMFA model offered guidances for further design and modification of the CB2receptor selective ligands.