The prefrontal cortex as a target for the atypical antipsychotic RU-31 with 5-HT2A antagonistic activity in the treatment of cognitive symptoms

Authors

DOI:

https://doi.org/10.18413/rrpharmacology.11.537

Abstract

Introduction: Cognitive deficits in schizophrenia are poorly managed by current antipsychotics, making the 5-HT2A receptor a promising therapeutic target, given its influence on dopaminergic signaling in the prefrontal cortex (PFC) and its involvement in cognitive processes. RU-31 (1-(2-diethylaminoethyl)-2-(4-methoxyphenyl)-imidazo[1,2-a]benzimidazole), a selective 5-HT2A antagonist, may offer cognitive benefits without the side effects associated with traditional dopamine-targeted therapies.

Materials and Methods: We evaluated RU-31 in Sprague-Dawley rats using molecular modeling, in vivo behavioral testing, and ex vivo electrophysiology. Molecular docking and dynamics simulations assessed the binding properties of RU-31 to the 5-HT2A receptor. The prepulse inhibition (PPI) paradigm (n=40) was used to test sensorimotor gating following a single RU-31 microinjection into the PFC. Patch-clamp recordings (n=32) from PFC pyramidal neurons were used to investigate RU-31's effects on serotonergic signaling.

Results: Molecular modeling indicated a strong binding affinity of RU-31 to the 5-HT2A receptor (100 ns). RU-31 (30 μg) restored PPI levels by 34.94% (p<0.05) following ketamine-induced deficits, suggesting an improvement in sensorimotor gating. In patch-clamp recordings, RU-31 (10 μM) significantly reduced 5-HT-mediated outward currents in layer 6 pyramidal neurons by 59.11% to 20.54 pA (SEM=7.12; SD=20.14; p<0.0211), indicating potent 5-HT2A antagonism and potential enhancement of downstream signaling.

Conclusion: This study establishes RU-31 as a promising therapeutic agent for the cognitive symptoms of schizophrenia, demonstrating that it reverses deficits in sensorimotor gating and normalizes PFC neuronal activity through selective 5-HT2A antagonism.

Graphical Abstract

Keywords:

atypical antipsychotics, 5-HT2A receptors, benzimidazoles, molecular docking, molecular dynamics, patch clamp, prepulse inhibition, prefrontal cortex, schizophrenia, cognitive deficits

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Author Contribution

Konstantin Y. Kalitin, Volgograd State Medical University

PhD, Associate Professor of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd, Russia; Senior Researcher, Laboratory of Metabotropic Drugs, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd, Russia; Senior Researcher, Laboratory of Synaptic Biology (Priority 2030) of Southern Federal University, Rostov-on-Don, Russia; e-mail: kkonst8@yandex.ru; ORCID ID: https://orcid.org/0000-0002-0079-853X. Conceptualization, setting primary objectives, carrying out experimental procedures, analyzing and interpreting the data, writing the initial draft of the article, contributing to the overall structure and design, finalizing the article for submission, designing visual data representations, applying statistical, mathematical, and computational methods for data analysis.

Olga Y. Mukha, Volgograd State Medical University

Assistant of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd, Russia; Junior Researcher, Laboratory of Metabotropic Drugs, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd, Russia; e-mail: myha14@gmail.com; ORCID ID: https://orcid.org/0000-0002-0429-905X. Task management, experimental work, literature review, data collection, drafting the manuscript, contributing to the scientific layout, ensuring the integrity and consistency of the entire article, including its final version; application of statistical, mathematical, and computational methods for data analysis, preparation of the final manuscript, interaction with the editors and reviewers.

Viktor B. Voynov, Southern Federal University

PhD, Chief Researcher at the Laboratory of Synaptic Biology (Priority 2030) of Southern Federal University, Rostov-on-Don, Russia; e-mail: vvoynov@sfedu.ru; ORCID ID:https://orcid.org/0000-0002-0242-6270. Literature review, drafting the manuscript, contributing to the scientific layout, ensuring the integrity and consistency of the entire article, including its final version; and preparation of the final manuscript.

Alexander A. Spasov, Volgograd State Medical University

PhD, Professor, Full member of the of the Russian Academy of Sciences; Head of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd, Russia; Head of the Department of Pharmacology and Bioinformatics, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd, Russia; e-mail: aaspasov@volgmed.ru; ORCID ID: https://orcid.org/0000-0002-7185-4826. Concept statement, supervision and mentorship, workflow control, critical revision with valuable intellectual investment, contributing to the overall structure and design, ensuring the integrity and consistency of the entire article.

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Published

30-09-2025

How to Cite

Kalitin KY, Mukha OY, Voynov VB, Spasov AA (2025) The prefrontal cortex as a target for the atypical antipsychotic RU-31 with 5-HT2A antagonistic activity in the treatment of cognitive symptoms. Research Results in Pharmacology 11(3): 98–108. https://doi.org/10.18413/rrpharmacology.11.537

Issue

Vol. 11 No. 3 (2025)

Section

Experimental Pharmacology

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Copyright (c) 2025 Kalitin KY, Mukha OY, Voynov VB, Spasov AA

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This work is licensed under a Creative Commons Attribution 4.0 International License.

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