Discovery of ONO-2920632 (VU6011887): A Highly Selective and CNS Penetrant TREK-2 (TWIK-Related K+ Channel 2) Preferring Activator <i>In Vivo</i> Tool Compound.

ABSTRACT: Herein we describe our initial work on the K₂P 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 EC₅₀ = 2.8 μM (95% E_max), TREK-2 EC₅₀ = 0.30 μM (184% E_max)), first-generation CNS penetrant (rat K_p = 0.37) in vivo tool compound with selectivity versus

SUBMITTER: Yashiro K 

PROVIDER: S-EPMC11887051 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature