The prefrontal cortex as a target for the atypical antipsychotic RU-31 with 5-HT2A antagonistic activity in the treatment of cognitive symptoms
Year: 2025
Type: article
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.
Source: Research Results in Pharmacology
Authors: Konstantin Y. Kalitin, Olga Y. Mukha, Viktor B. Voynov, Alexander A. Spasov
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7086745493
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