Hybrid molecules combining GABA-A and serotonin 5-HT6 receptors activity designed to tackle neuroinflammation associated with depression


European Journal of Medicinal Chemistry


Monika Marcinkowska, Barbara Mordyl, Nikola Fajkis-Zajaczkowska, Agata Siwek, Tadeusz Karcz, Alicja Gawalska, Adam Bucki, Paweł Żmudzki, Anna Partyka, Magdalena Jastrzębska-Więsek, Bartosz Pomierny, Maria Magdalena Smolik Karolina Pytka, Kamil Mika, Magdalena Kotańska, Marcin Kolaczkowskia



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-HT6 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-HT6 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 interesting pharmacological profile of 3B makes it a promising candidate for further development for depression associated with neuroinflammation.

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