| Summary: | The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α<sub>2</sub>-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT<sub>7</sub> receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α<sub>2</sub>-adrenoceptors and 5-HT<sub>7</sub> receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound <b>8</b> behaved as a potent α<sub>2A</sub>/5-HT<sub>7</sub> receptor antagonist and displayed moderate-to-high selectivity over α<sub>1</sub>-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound <b>8</b> improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.
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