Faculty Collaboration Database

Fine-tuning 5-HT₇ receptor selectivity, inverse agonism, and metabolic stability of new (aryloxy)ethyl-piperidines toward antidepressant and pro-cognitive properties. Eur J Med Chem 2026 Jan 15;302(Pt 3):118369

Date

11/26/2025

Pubmed ID

41289819

Pubmed Central ID

PMC12698111

DOI

10.1016/j.ejmech.2025.118369

Scopus ID

2-s2.0-105022479120 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

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.

Author List

Canale V, Blicharz-Futera K, Bijata M, Cavalco NG, Partyka A, Stefaniak M, Kamiński M, Satała G, Warszycki D, Lanham JK, Gołębiowska J, Gawlik M, Smolik M, Bijata K, Jastrzębska-Więsek M, Kurczab R, Bojarski AJ, Walczak M, McCorvy JD, Włodarczyk J, Popik P, Zajdel P

Author

John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antidepressive Agents
Cognition
Dose-Response Relationship, Drug
Humans
Male
Mice
Molecular Structure
Piperidines
Rats
Receptors, Serotonin
Structure-Activity Relationship