Based on the finding that concurrent blockade of α2-AR and 5-HT7R might be beneficial in the treatment of depressive disorders, we elaborated a medicinal mechanochemical approach to provide a limited series of arylsulfonamides of (dihydrobenzofuranoxy)ethyl piperidines as dual acting α2/5-HT7R antagonists. This evidence concerns the gene ADORA2A and depressive disorder.