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Vol. 27, Art. 6 (pp. 97-139)    |    2026       

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The problem of extrapolating the effects of kappa opioid receptor agonists from animals to humans (Literary review)

Subbotina S.N., Shcherbinina K.E., Yudin M.A., Nikiforov A.S.

Federal State Budgetary Institution “State Research Testing Institute of Military Medicine” of the Ministry of Defense of the Russian Federation, St. Petersburg 195043, St Petersburg, st. Lesoparkovaya, 4

Brief summary

The paper analyzes the literature data on the problem of extrapolating the effects of kappa-opioid receptor agonists from animal models to humans. 74 publications were analyzed from 1967 to 2025, of which 54 were published from 2010 to 2025 years. It was found that structural and functional differences of the kappa-opioid neurotransmitter system the pharmacodynamics parameters of the ligand-receptor interaction functional selectivity and the rate of metabolic processes determine the divergence of effects and the difficulty of adequately transferring experimental data to humans. The extrapolation of the results is complicated by the fact that many effects of kappa-opioid receptor agonists including psychotropic ones are extremely difficult to simulate in animals models. Demonstrated that in the preclinical assessment it is important to introduce technology for humanizing animals expressing human KOR variants, followed by comparative studies on primates whose opioid system is phylogenetically closer to humans. In addition, it is necessary to take into account not only the pharmacodynamics characteristics of the compound and its penetrating ability through the BBB. An important aspect is the degree of protein binding the peculiarities of metabolism in different animal species and the choice of matrix (whole blood, plasma or serum) when studying the pharmacokinetics of KOR agonists. It has been established that the combination of experimental (biometric with the introduction of correction coefficients) and computational extrapolation methods (physiologically based pharmacokinetic modelling) is a key strategy for the correct transfer of the effects if KOR agonists into clinical practice. Molecular imaging makes it possible to significantly correct the predicted dose values for clinical trials.


Key words

kappa-opioid receptor agonists, relevant animal models, psychotropic effect, interspecific differences, extrapolation of the effects of kappa- opioid receptor agonist.

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