Design And Optimization Of Novel Selective Agonists For The CB2 Receptor

Cannabinoid receptors CB1 and CB2 belong to GPCR family and are widely distributed in body.CB1 is mainly distributed in the central nervous system,while CB2 is mainly distributed in the peripheral system.Studies have shown that CB2,as a drug target,is very popular because it has no central nervous side effects.It plays an important role in vivo and is related to the occurrence and development of inflammation and tumors.At present,although many CB2 ligands are in the stage of clinical research,there is still no corresponding drug on the market.Therefore,the study of CB2 selective ligands is of great significance,especially the study of CB2 agonists.Although there are many kinds of CB2 ligands,their physicochemical properties are not ideal,especially their high liposolubility(CLogP>5)leads to poor pharmacokinetic properties,which is not conducive to the role of the immune system.Therefore,it is particularly important to design and optimize ligands with high activity,strong selectivity and good pharmaceutical properties.LogP of oil-water partition coefficient and molecular docking simulation of receptor-ligand interaction mode are very important information,which have directive significance for the design of CB2 selective agonists with better ADME.In this paper,the LogP values of CB2 agonists with good activity were determined by high performance liquid chromatography.The results showed that the LogP values of the compounds ranged from 3 to 4,which was basically consistent with the predicted value of CLogP,indicating that the strategy of reducing fat solubility of CB2 agonists was reasonable and feasible.At the same time,in collaboration with other topics,based on the CB2 structure model established earlier,we simulated the interaction mode between CB2 ligand and receptor using flexible molecular docking method,predicted the type of molecular interaction with key amino acids,and understood the structure-activity relationship.As the main participants,the above results were published in Eur.J.Med.Chem.and J.Med.Chem.respectively,which contributed greatly to the publication of the paper.At the same time,these studies also provide a theoretical basis for further research and development of lower fat-soluble CB2 ligands.In order to further develop low-fat-soluble(1<LogP<3)CB2 agonists with better biological activity and selectivity,based on the above research results,using the basic principles and methods of drug design,combining with the knowledge of pharmacochemistry,through skeleton transition and electron exchange,and on the basis of the previous research and development of CB2 selective ligands,molecular simulation prediction model was used to design molecules.There is a parallel π-πinteraction between the side chain of the key residue W258 and F117 as an agonist rather than an antagonist.At the same time,hydrophilic groups were introduced without affecting the interaction between the key molecules of CB2.The CLogP predicted by XLogP was used to further guide the design of compounds,improve the water solubility of molecules and reduce the LogP of oil-water partition coefficient.In this paper,the structure of the lead compounds was modified and optimized,and three mother-nucleus derivatives including quinoxaline,pyrimidine Dione and quinazoline Dione were synthesized.A total of 40 new structural compounds were synthesized.The biological activities of these new compounds against CB1 and CB2 are being carried out at the National Center for New Drug Screening.