Study of aversive and p38 mapk-inhibitory properties of kappa-agonist with analgesic activity – compound RU-1205
| Autor: | Edwin Zvartau, Olga A. Dravolina, Alexander A. Spasov, V. A. Anisimova, Olesya Iu. Grechko, Yuliya V. Semenova, Natalya V. Eliseeva, Pavel M Vasiliev |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pharmacology Agonist kappa-opioid receptor aversion dysphoria kappa-opioid receptor p38 MAPK-kinase medicine.drug_class Chemistry p38 mitogen-activated protein kinases Analgesic RM1-950 Inhibitory postsynaptic potential 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine aversion Pharmacology (medical) Therapeutics. Pharmacology p38 MAPK-kinase 030217 neurology & neurosurgery Kappa dysphoria |
| Zdroj: | Research Results in Pharmacology 6(3): 59-65 Research Results in Pharmacology, Vol 6, Iss 3, Pp 59-65 (2020) |
| ISSN: | 2658-381X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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