Hybrid molecules combining GABA-A and serotonin 5-HT 6 receptors activity designed to tackle neuroinflammation associated with depression

There is clear evidence that the presence of inflammatory factors and impaired GABA-ergic neurotransmission in depressed patients is associated with poor clinical outcome. We designed hybrid molecules, bearing the GABA molecule assembled with chemical fragments that interact with the serotonin 5-HT...

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Published in:European journal of medicinal chemistry 2023-02, Vol.247, p.115071
Main Authors: Marcinkowska, Monika, Mordyl, Barbara, Fajkis-Zajaczkowska, Nikola, Siwek, Agata, Karcz, Tadeusz, Gawalska, Alicja, Bucki, Adam, Żmudzki, Paweł, Partyka, Anna, Jastrzębska-Więsek, Magdalena, Pomierny, Bartosz, Walczak, Maria, Smolik, Magdalena, Pytka, Karolina, Mika, Kamil, Kotańska, Magdalena, Kolaczkowski, Marcin
Format: Article
Language:English
Subjects:
Antidepressive Agents - pharmacology
Antidepressive Agents - therapeutic use
Depression - drug therapy
gamma-Aminobutyric Acid
Humans
Neuroinflammatory Diseases
Serotonin
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Summary:There is clear evidence that the presence of inflammatory factors and impaired GABA-ergic neurotransmission in depressed patients is associated with poor clinical outcome. We designed hybrid molecules, bearing the GABA molecule assembled with chemical fragments that interact with the serotonin 5-HT receptor. Such a combination aimed to curb neuroinflammation, remodel GABA-ergic signaling, and provide antidepressant-like activity. The most promising hybrid 3B exerted nanomolar affinity for 5-HT receptors and exerted agonistic properties on GABA-A receptors. Developability studies conferred that 3B exerted favorable drug-like properties and optimal brain penetration. In in vivo studies, 3B exerted robust antidepressant-like activity and proved to be highly effective in reducing levels of oxidative stress markers and the pro-inflammatory cytokine IL-6. The inetersting pharmacological profile of 3B makes it a promising candidate for further development for depression associated with neuroinflammation.
ISSN:1768-3254