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 receptor activity. The serotonin 5-HT 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 showed a desirable receptor profile and physicochemical properties. In pharmacological studies, was able to reduce the secretion of proinflammatory cytokines and decrease oxidative stress markers. In animal studies, exerted antidepressant-like activity deriving from a synergic interplay between 5-HT and GABA-A receptors. Altogether, the presented findings point to hybrid as an interesting tool that interacts with pharmacologically relevant targets, matching the pathological dysfunction of depression associated with neuroinflammation.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10119930PMC
http://dx.doi.org/10.1021/acschemneuro.3c00033DOI Listing

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