Ion channel modulators hold enormous promise for treating neurological and psychiatric conditions, but a lack of selective, in vivo proof-of-concept tool compounds have hampered drug development efforts. Now, after more than a decade of collaboration, researchers from Vanderbilt University’s Warren Center for Neuroscience Drug Discovery and Japan’s Ono Pharmaceutical have delivered a powerful proof-of-concept: first-in-class TREK channel modulators with applications in pain relief and cognitive enhancement.
The K2P family of “leak” channels, two-pore domain potassium channels, has been pharmacologically elusive. But as outlined in two new studies published in ACS Chemical Neuroscience and ACS Medicinal Chemistry Letters, the Vanderbilt-Ono team has created highly selective, brain-penetrant tool compounds—one that activates TREK-2 channels and one that inhibits TREK-1/2 channels—that unlock entirely new paths for translational neuroscience research.
“Industry-academic partnerships are powerful when each side brings complementary strengths,” Craig Lindsley said. Lindsley is the principal investigator on both studies and the director of WCNDD. “The joint research teams at Ono and Vanderbilt brought tremendous and diverse expertise in ion channel pharmacology, medicinal chemistry, DMPK and behavior. That fusion led to real breakthroughs.” DMPK refers to the drug metabolism and pharmacokinetic studies that help researchers determine whether their compounds warrant further study as potential therapeutics.
In the first study, a compound called ONO-2920632 (VU6011887) emerged as a potent and selective TREK-2 activator. When given to mice, it was as effective as standard nonsteroidal anti-inflammatory drugs in reducing pain, but it did so without the side effects commonly seen with opioids.
The second study introduced ONO-TR-772 (VU6018042), a TREK-1/2 inhibitor that enhanced cognitive performance in mice subjected to memory deficits induced by a drug called MK-801—a model for schizophrenia-related cognitive impairment. With a low minimum effective dose, ONO-TR-772 reversed deficits and matched the efficacy of antipsychotic drugs in a standard novel object recognition test.
What makes these results exceptional isn’t just the compounds themselves, it’s what they represent: the value of translational research grounded in real-world therapeutic goals. The WCNDD-Ono collaboration wasn’t just academic, it was licensed and funded with the long-term aim of generating clinical candidates. Still, the partners chose to release these best-in-class in vivo tool compounds to the scientific community to accelerate further discovery.
“These are not just best-in-class TREK ligands, they’re essential tools that other researchers can use to probe pain pathways, cognitive mechanisms, and psychiatric models, filling a critical gap in preclinical neuroscience,” Lindsley said.
The success of these TREK modulators has roots in earlier collaborations as well. A key insight—replacing a benzyl alcohol linker with an acetylene group—came from prior work with Janssen, underscoring how even “small” chemical choices can pivot entire programs.
Next up? Clinical translation. With their potent in vivo activity and clean pharmacology profiles, both compounds will serve as the foundation for next-generation compounds that evolve into first-in-human studies.
In the meantime, they serve as a reminder: When discovery is shared, progress multiplies.
Haruto Kurata, a visiting Ono research fellow in the Lindsley lab, Darren Engers, research assistant professor of pharmacology, and Jerod Denton, professor of pharmacology, were co-authors on both studies.
Go deeper:
The article “Discovery of ONO-TR-772 (VU6018042): A Highly Selective and CNS Penetrant TREK Inhibitor in Vivo Tool Compound” was published in ACS Medicinal Chemistry Letters in April 2025.
The article “Discovery of ONO-2920632 (VU6011887): A Highly Selective and CNS Penetrant TREK-2 (TWIK-Related K+ Channel 2) Preferring Activator In Vivo Tool Compound” was published in ACS Chemical Neuroscience in February 2025.
Funding:
This research was supported by William K. Warren Jr. and the William K. Warren Foundation.