| Pain,as the most common clinical conditions,is one of the major factors that people seek for medical services.The analgesic drugs which are normally used in the market can cause harmful side effects and the treatment effect is not satisfactory.Many studies have reported that Cannabinoid Receptor type 2（CB2）is mainly distributed in the peripheral organized system and immune system.When CB2 is selectively activated,pain can be effectively suppressed,and the central nervous system side effects caused by activating the CB1 can be avoided.This strategy of receptor selective activation coincides with the current research direction of analgesic drugs development.Currently available cannabinoids are not selective and there is a threat of central nervous system side effects.The clinical research of selective CB2 agonists has made some progress.However,most of the compounds have poor efficacy because of structural defects.Therefore,it is necessary to develop novel and selective CB2 agonists with better structure.In this article,two series of new CB2 agonists have been designed and synthesized based on the reported CB2 agonists.The chemical synthesis methods are convenient,the conditions are mild and the yields are stable.After cell screening,the compound e16 in the pyrimidine-linked urea series had the best activity of this series with an EC50 of 609 nM(Emax=70%).The EC50 values for compounds o17 and o41 in the 3-tert-butyl-5-carboxamide pyrazole ring series were 207 nM(Emax=100%)and 103 nM(Emax=100%),respectively.And the CB1 agonistic activity of this series of compounds are all greater than 10μM,demonstrating that the compounds have good selectivity.In addition,two compounds（o17 and o41）were tested for confirmatory experiments,confirming that the designed compounds are targeted to CB2.The results of this study contribute to the further structural exploration and new analgesic drug development of CB2 agonists in the future. |
