2025/02/21 by Kentaro Yashiro, Yuzo Iwaki, H Urata +13 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · Neuroscience · #Cardiac electrophysiology and arrhythmias #Ion channel regulation and function #Neuroscience and Neuropharmacology Research
paper · pdf · doi:10.1021/acschemneuro.5c00032
openalex publication_date 2025/02/21 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28
High Resolution Image Download MS PowerPoint Slide Herein we describe our initial work on the K 2 P family of potassium ion channels with the chemical optimization and characterization of a novel series of TWIK-Related K+ Channel (TREK)-1/2 dual activators and TREK-2 preferring activators derived from a high-throughput screening hit. The exercise provided TREK activators with good CNS penetration and others with low CNS exposure to enable exploration of both central and peripheral TREK activation. From this, ONO-2920632 (VU6011887 = 19b ) emerged as a reasonably potent (human Tl +; TREK-1 EC 50 = 2.8 μM (95% E max ), TREK-2 EC 50 = 0.30 μM (184% E max )), first-generation CNS penetrant (rat K p = 0.37) in vivo tool compound with selectivity versus the other K 2 P channels (>91-fold selective vs TASK1, TASK2, TASK3, TRAAK, TWIK2, and 31-fold selective vs TRESK) and no significant activity in a large ancillary pharmacology panel. ONO-2920632 (VU6011887) displayed robust, dose dependent efficacy when dosed orally in a mouse pain model (acetic acid writhing assay), where it was equipotent at 3 mg/kg to the assay standard indomethacin at 10 mg/kg. The therapeutic potential of TREK channel activation has long been hampered by a lack of selective, small molecule tools, and this work provides a variety of in vivo tool compounds for the community.