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

Authors

DOI:

https://doi.org/10.3897/rrpharmacology.6.54558

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.

Keywords:

aversion, dysphoria, kappa-opioid receptor, p38 MAPK-kinase

Author Contribution

Alexander A. Spasov, Volgograd State Medical University of the Ministry of Health of the Russian Federation

Doctor Habil. in Medical Sciences, Full Professor, Academician of the Russian Academy of Sciences, Head of the Department of Pharmacology and Bioinformatics.

Edwin E. Zvartau, A.V. Waldman Research Institute of Pharmacology of I.P. Pavlov First St. Petersburg State Medical University of the Ministry of Health of the Russian Federation

Doctor Habil. in Medical Sciences, Full Professor, Head of the Department of Pharmacology.

Olesya Iu. Grechko, Volgograd State Medical University of the Ministry of Health of the Russian Federation

Doctor Habil. in Medical Sciences, Full Professor of the Department of Pharmacology and Bioinformatics.

Natalya V. Eliseeva, Volgograd State Medical University of the Ministry of Health of the Russian Federation

PhD in Medical Sciences, Associate Professor of the Department of Pharmacology and Bioinformatics.

Yuliya V. Semenova, Volgograd State Medical University of the Ministry of Health of the Russian Federation

PhD student in Medical Sciences, Assistant Professor of the Department of Pharmacology and Bioinformatics.

Olga A. Dravolina, A.V. Waldman Research Institute of Pharmacology of I.P. Pavlov First St. Petersburg State Medical University of the Ministry of Health of the Russian Federation

PhD in Biological Sciences, Head of the Laboratory for Experimental Pharmacology of Addictive States.

Pavel M. Vasiliev, Volgograd State Medical University of the Ministry of Health of the Russian Federation

Doctor Habil. in Biological Sciences, Full Professor of the Department of Pharmacology and Bioinformatics.

Vera A. Anisimova, Research Institute of Physical and Organic Chemistry, Southern Federal University, (IPOC)

PhD in Chemical Sciences.

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Published

25-09-2020

How to Cite

Spasov AA, Zvartau EE, Grechko OI, Eliseeva NV, Semenova YV, Dravolina OA, Vasiliev PM, Anisimova VA (2020) Study of aversive and p38 mapk-inhibitory properties of kappa-agonist with analgesic activity – compound RU-1205. Research Results in Pharmacology 6(3): 59–65. https://doi.org/10.3897/rrpharmacology.6.54558

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Review article

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