2. Academic Validation
  3. Design and validation of novel brain-penetrant HCN channel inhibitors to ameliorate social stress-induced susceptible phenotype

Design and validation of novel brain-penetrant HCN channel inhibitors to ameliorate social stress-induced susceptible phenotype

  • Mol Psychiatry. 2025 Apr 8. doi: 10.1038/s41380-025-02972-8.
Emily M Teichman # 1 2 3,  Jianping Hu # 1,  Hsiao-Yun Lin 2 3,  Rachel L Fisher-Foye 2 3,  Anthony Blando 2 3,  Xiaoping Hu 1,  H Ümit Kaniskan 1,  Sarah E Montgomery 1 2 3 4,  Min Cai 2 3,  Lyonna F Parise 2 3,  Jun Wang 2 5 6,  Scott J Russo 2 3 7,  Ming-Hu Han 8 9 10 11,  Jian Jin 12 13 14 15,  Carole Morel 16 17
Affiliations

Affiliations

  • 1 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 2 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 3 Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 4 Modendo Inc., 3415 Colorado Ave, Boulder, Colorado, 80303, USA.
  • 5 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 6 Geriatric Research, Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, New York, NY, USA.
  • 7 Brain-Body Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 8 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. ming-hu.han@mssm.edu.
  • 9 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. ming-hu.han@mssm.edu.
  • 10 Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. ming-hu.han@mssm.edu.
  • 11 Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology; Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China. ming-hu.han@mssm.edu.
  • 12 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. jian.jin@mssm.edu.
  • 13 Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. jian.jin@mssm.edu.
  • 14 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. jian.jin@mssm.edu.
  • 15 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. jian.jin@mssm.edu.
  • 16 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. carole.morel@mssm.edu.
  • 17 Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. carole.morel@mssm.edu.
  • # Contributed equally.
PMID: 40199995 DOI: 10.1038/s41380-025-02972-8
Abstract

Major Depressive Disorder (MDD) is a devastating, multifactorial disease with limited pharmacological treatment options. Patients with MDD exhibit alterations in their dopamine (DA) signaling pathways through the midbrain ventral tegmental area (VTA). A similar observation is also detected in preclinical models of stress - mice exhibit behavioral and physiological impairments following chronic social defeat stress (CSDS). Prior studies demonstrate that CSDS-susceptible mice have increased VTA DA neuronal excitability, in part driven by an upregulation in hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. Inhibiting HCN channels with known inhibitors such as Cilobradine alleviates the negative behavioral effects of CSDS. Here, we aimed to identify Cilobradine analogs with improved neural tropism and inhibitory efficacy. Two compounds, MS7710 and MS7712, differing by their left-hand side moieties, have a similar, potent inhibitory effect on VTA DA Ih currents as compared to Cilobradine, and a greater inhibitory effect than Cilobradine on VTA DA firing rate. We demonstrate that MS7710 and MS7712 have superior brain/plasma concentration ratios as compared to Cilobradine. They were efficacious at inhibiting VTA DA neuron firing rate and bursting activity in CSDS-susceptible male mice at lower doses than Cilobradine, which was recapitulated in female CSDS-susceptible mice with MS7710. Finally, we define that a single intraperitoneal injection of MS7710 ameliorates CSDS-induced social interaction deficits and reward-associated cognitive inflexibility for at least two weeks in male and female mice. These findings yield a novel HCN Channel Inhibitor with improved neural tropism and stress-alleviating effects that could provide a basis for future antidepressant drug discovery.

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