Preliminary Study On The Effects And Mechanisms Of Different Structure-activity Relationships Of Indole Synthetic Cannabinoids JWH-018 And JWH-019 On The Neuropsychiatric Disorders

Objective: Synthetic cannabinoids are currently one of the most heavily abused drugs worldwide.In this study,we focus on whether there are differences in the effects of synthetic cannabinoids(SCs)JWH-018 and JWH-019 on cannabinoid-induced neuropsychiatric damage,and elucidate the receptor mechanisms that produce the differences,so as to provide a new paradigm and ideas for the study of SCs and lay the theoretical and experimental foundation for later studies.Methods:1.JWH-018 and JWH-019 were injected intraperitoneally,and the mice were tested for activity,body temperature,pain threshold,and addiction using the spontaneous activity test,homecage behavior test,hot plate test and conditioned place preference test;The zebrafish were tested for activity and hallucinogenicity using the spontaneous activity test and mirror image test.2.Using the CB1 receptor antagonist AM251 and the CB2 receptor antagonist AM630 to block the corresponding receptors,we elucidated the receptor mechanisms that produce the above behavioral changes.3.Through molecular docking of six selected SCs,including JWH-018 and JWH-019,the binding mode and conformational characteristics of the SCs and CB1 receptor were explained,the relevant mechanism of the binding of SCs and CB1 receptor was expounded,and the relationship between structure-activity and behavior was further discussed.Results:1.JWH-018 administered mice showed significantly lower total activity distance in spontaneous activity and homecage behavior experiments in a dosedependent manner.Body temperature in the temperature-pain threshold experiment was significantly lower and pain threshold was higher.The conditioned place preference test assay did not produce a preference for the companion drug side,suggesting that JWH-018 is not addictive.JWH-019 administered mice did not show significant differences in any of the above experiments,except for a slight decrease in body temperature.2.JWH-018 administered zebrafish showed no significant difference in the total distance travelled in the spontaneous activity experiment.The redu-ced residence time in the center of the mirror area in the mirror experiment suggests that JWH-018 causes hallucinogenic behavior in zebrafish.JWH-019 administered zebrafish did not show significant differences in the above experiments.3.The CB1 receptor antagonist AM251 inhibited the decrease in activity,decrease in body temperature and increase in pain threshold caused by JWH-018 and blocked the hallucinogenic effects of JWH-018;The CB2 receptor antagonist AM630 does not block the the hallucinogenic effects of JWH-018.4.Six kinds of indole SCs,including JWH-018 and JWH-019,with subtle structural differences in the head and tail,were molecular-docked with CB1 receptor,and the SCs combined with CB1 receptor to form different stereo conformations.Conclusions:1.JWH-018 inhibits activity in mice and has a psychotropic effect,mainly mediated by CB1 receptors.JWH-019 had no significant effect.2.The behavioral differences between JWH-018 and JWH-019 may be caused by the different spatial conformations formed after binding to CB1 receptors.