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Vol. 24, Art. 38 (pp. 498-515)    |    2023       

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Neurotoxic profile of kappa-opioid receptor agonist from the class of alkyl-substituted piperazine derivatives

Subbotina S.N.1, Vakhviyaynen М.S.1, Yudin М.А.1,2

1 Federal State Budgetary Institution State Research Testing Institute of Military Medicine of the Ministry of Defense of the Russian Federation

2 Federal State-Funded Education Institution of Higer Professional Education North-Western State Medical University named after I. I. Mechnikov (NWSMU), Ministry of Health of the Russian Federation

Brief summary

The article carried out an experimental assessment of the neurotoxic profile of an alkyl-substituted piperazine derivative DPI-3290, which is a highly selective kappa-opioid receptor agonist with pronounced analgesic properties. The role of non-opioid neurotransmitter systems in the mechanisms of the toxic action of DPI-3290 was traced. It has been shown that the side effects of an alkyl-substituted piperazin derivative are determined by an activating effect on adrenergic system and blocking action against dopaminergic and GABA-ergic neurotransmission. The ability of DPI-3290 to influence the reuptake of dopamine by increasing the concentration of the active dopamine transporter in the cerebral cortex and cerebellum was established, creating a deficiency of the extracellular mediator in the first day after exposure. Demonstrated the absence of the effect of kappa-opioid receptor agonist on the serotonin and acetylchloline system when exposed to doses not exceeding the average effective for the development of sedation in rodents. The obtained data can be used in the development of new analgesic compounds based on piperazine derivatives. In particular, at the preclinical stage of screening of newly synthesized compounds, it is advisable to select kappa-opioid receptor agonists with the least activity against adrenergic, dopaminergic and GABA-ergic neurotransmission.


Key words

kappa-opioid receptor agonist; derivative of alkyl-substituted piperazines; side effects; pharmacological probes; non-opioid neurotransmitter systems

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