Dual Molecules Targeting 5-HT6 and GABA-A Receptors as a New Approach to Combat Depression Associated with Neuroinflammation


ACS Chemical Neuroscience


Marcinkowska, M., Mordyl, B., Siwek, A., Głuch-Lutwin, M., Karcz, T., Gawalska, A., Sapa, M., Bucki, A., Szafran, K., Pomierny, B., Pytka, K., Kotan, M., Mika, K., & Kolaczkowski, M. (2023). Dual Molecules Targeting 5-HT 6 and GABA-A Receptors as a New Approach to Combat Depression Associated with Neuroinflammation. Cite This: ACS Chem. Neurosci, 14, 1474–1489.



While monoaminergic deficits are evident in all depressed patients, nonresponders are characterized by impaired GABA-ergic signaling and the simultaneous presence of the inflammatory component. Pharmacological agents able to curb pathological immune responses and modulate ineffective GABA-ergic neurotransmission are thought to improve therapeutic outcomes in the treatment-resistant subgroup of depressed patients. Here, we report on a set of dually acting molecules designed to simultaneously modulate GABA-A and 5-HT 6 receptor activity. The serotonin 5-HT 6 receptor was chosen as a complementary molecular target, due to its promising antidepressant-like activities reported in animal studies. Within the study we identified that lead molecule 16 showed a desirable receptor profile and physicochemical properties. In pharmacological studies, 16 was able to reduce the secretion of proinflammatory cytokines and decrease oxidative stress markers. In animal studies, 16 exerted antidepressant-like activity deriving from a synergic interplay between 5-HT 6 and GABA-A receptors. Altogether, the presented findings point to hybrid 16 as an interesting tool that interacts with pharmacologically relevant targets, matching the pathological dysfunction of depression associated with neuroinflammation.

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