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

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. doi: 10.1016/j.ejmech.2025.118369.
Vittorio Canale 1,  Klaudia Blicharz-Futera 2,  Monika Bijata 3,  Natalie G Cavalco 4,  Anna Partyka 5,  Matylda Stefaniak 6,  Michał Kamiński 2,  Grzegorz Satała 7,  Dawid Warszycki 7,  Janelle K Lanham 4,  Joanna Gołębiowska 8,  Maciej Gawlik 9,  Magdalena Smolik 9,  Krystian Bijata 3,  Magdalena Jastrzębska-Więsek 5,  Rafał Kurczab 7,  Andrzej J Bojarski 7,  Maria Walczak 9,  John D McCorvy 10,  Jakub Włodarczyk 3,  Piotr Popik 8,  Paweł Zajdel 6
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, Jagiellonian University Medical College, 9 Medyczna Str., 30-688, Krakow, Poland. Electronic address: [email protected].
  • 2 Department of Organic Chemistry, Jagiellonian University Medical College, 9 Medyczna Str., 30-688, Krakow, Poland; Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, 16 St. Łazarza Str., 31-530, Krakow, Poland.
  • 3 Laboratory of Cell Biophysics, Nencki Institute of Experimental Biology, 3 Pasteur Str., 02-093, Warsaw, Poland.
  • 4 Department of Cell Biology, Neurobiology & Anatomy, Neuroscience Research Center, Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI, 53226, United States.
  • 5 Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688, Krakow, Poland.
  • 6 Department of Organic Chemistry, Jagiellonian University Medical College, 9 Medyczna Str., 30-688, Krakow, Poland.
  • 7 Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Str., 31-343, Krakow, Poland.
  • 8 Department of Behavioral Neuroscience & Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Str., 31-343, Krakow, Poland.
  • 9 Department of Toxicology, Jagiellonian University Medical College, 9 Medyczna Str., 30-688, Krakow, Poland.
  • 10 Department of Cell Biology, Neurobiology & Anatomy, Neuroscience Research Center, Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI, 53226, United States; Department of Pharmacology and Toxicology, Neuroscience Research Center, Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI, 53226, United States.
PMID: 41289819 DOI: 10.1016/j.ejmech.2025.118369
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.

Keywords

5-HT(7) receptor inverse agonists; Affective disorders; Antidepressant-like effects; MMP-9; Pro-cognitive properties.

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