Fine-tuning 5-HT7 receptor selectivity, inverse agonism, and metabolic stability of new (aryloxy)ethyl-piperidines toward antidepressant and pro-cognitive properties.

Affective disorders, the leading causes of disability and premature death worldwide, require new and effective treatment strategies. Clinically used antidepressants and second-generation antipsychotic drugs, including vortioxetine and lurasidone, act as potent 5-HT7 receptor antagonists and improve cognitive functions in the patients with mood disorders. Additionally, 5-HT7 receptor-mediated activation of matrix metalloproteinase 9 (MMP-9) induces depressive-like behavior in mice. We designed and synthesized a series of 27 arylsulfonamide derivatives of 2-[(2-aryl/2-heteroaryl)phenoxy]ethyl-piperidines and examined their in vitro and in vivo effects. These compounds are closely related to the previously reported 5-HT7 receptor ligand (PZ-1129), developed in our laboratories. Our goal was to investigate the impact of heterocyclic ring replacement on receptor selectivity and metabolic stability, because the aryloxyl moiety was postulated to determine affinity for serotonin and dopamine receptors, and interactions with metabolizing enzymes. The study identified compound 57 as a potent, selective and metabolically stable 5-HT7 receptor inverse agonist of Gs signaling pathway. Bioavailable compound 57 shortened immobility in the forced swim test in mice and reversed PCP-induced cognitive deficits in the novel object recognition test in rats suggesting antidepressant-like and pro-cognitive effects. In addition, compound 57 reduced 5-HT7 receptor-mediated MMP-9 activity in the mouse hippocampus with efficacy comparable to the reference 5-HT7 receptor antagonist, SB-269970, further suggesting its purported antidepressant-like actions. These findings support the potential therapeutic application of targeting 5-HT7 receptor/MMP-9 signaling pathway for the treatment of affective disorders.