Study of aversive and p38 mapk-inhibitory properties of kappa-agonist with analgesic activity – compound RU-1205

Abstract

Introduction: The clinical use of kappa-opioid agonists, despite their lack of significant drug potential, is limited by the development of severe sedation, dysphoria, depression, and anhedonia. To this date, there are kappa-opioid receptor agonists lacking these side effects due to the selective activation of intracellular signal transmission pathways without p38-MAPK-kinase activation.
 Materials and methods: We analyzed assessment of the docking energy of compound RU-1205 to the p38-MAPK ac­tive center by the method of similarity to SB203580. The study of possible aversive properties of RU-1205 (0.01–1 mg/kg s.c.) conducted in the tests of the intravenous self-administration and drug differentiation with butorphanol (0.01–0.3 mg/kg). The study of p38 MAPK-inhibitory activity was studied by the ability of RU-1205 to change the aversive prop­erties of U50488 (10 mg/kg i.p.) compared to MAPK-kinase inhibitor SB203580 in the conditioned place avoidance test.
 Results: The spatial similarity coefficient of the RU-1205 molecule with SB203580 by the molecular conformation method was 1.14 (high similarity), and the docking energy was -8.7 Kcal/mol. RU-1205 did not possess any properties similar to those of butorphanol and did not demonstrate any primary reinforcing aversive properties in the development of intravenous self-administration reaction. Compound RU-1205 did not demonstrate any aversive properties in the condi­tioned place avoidance test, and reduced the development of aversion caused by U-50488, when they were used together.
 Discussion: The in silico analysis suggested that, in addition to agonism towards the kappa-opioid receptor, RU-1205 com­pound exhibits the properties of a p38 MAPK kinase inhibitor, which means it may have a double pharmacological activity.
 Conclusion: Kappa agonist – compound RU-1205 – is not a trigger of the development of behavioral patterns in ani­mals corresponding to the development of addiction/dysphoria. The mechanism of such an activity may be associated with an inhibitory effect of compound RU-1205 on neuronal p38-MAPK-kinase.