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

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 inefl'ective 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-HT6 receptor activity. The serotonin 5-HT6 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 acti v i t y deriving from a synergic interplay between 5-HT6 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.

Automated summary

In this study, a set of dually acting molecules were designed to modulate GABA-A and 5-HT6 receptor activity simultaneously, aiming to improve therapeutic outcomes in treatment-resistant depression. Lead molecule 16 showed desirable receptor profile and physicochemical properties, reducing proinflammatory cytokine secretion and oxidative stress markers. Animal studies demonstrated antidepressant-like activity of 16 through synergic interplay between 5-HT6 and GABA-A receptors. These findings suggest that hybrid molecule 16 is an interesting tool that interacts with pharmacologically relevant targets, matching the pathological dysfunction of depression associated with neuroinflammation.