Author: Cen, Yao ; Zhang, Fan ; Wang, Chengyan ; Zhou, Jie ; Xie, Yiming ; Wei, Ziyi ; Zheng, Xiaotong ; Wang, Xiaoyu ; Liu, Kaiyue ; Xu, Bailing ; Ji, Yunyun

TREK-1 regulates neuronal excitability and neuronal cell apoptosis, and inhibition of TREK-1 is a potential strategy to prevent cell death and achieve neuroprotection in an ischemic stroke. In this work, a series of novel isobenzofuran-1(3H)-one derivatives were designed and synthesized as TREK-1 inhibitors, and extensive structure-activity relationships led to the discovery of potent and selective TREK-1 inhibitors having IC₅₀ values of a low micromolar level. Among them, Cpd8l potently and selectively inhibited TREK-1 (IC₅₀ = 0.81 μM, selectivity >30 fold over other K⁺, Na⁺, and TRP channels). Cpd8l remarkably reduced the neuron death in the OGD/R-induced cortical neuronal injury model, while adenovirus silencing TREK-1 reduced its neuroprotective effect. Furthermore, Cpd8l could effectively ameliorate brain injury in MCAO/R model mice. Collectively, this work demonstrates that Cpd8l may serve as a novel lead compound to develop a highly potent and selective TREK-1 inhibitor for ischemic stroke treatment.

01 Aug 2012·American Journal of Physiology-Gastrointestinal and Liver PhysiologyQ3 · MEDICINE

Relative contribution of SK_Ca and TREK1 channels in purinergic and nitrergic neuromuscular transmission in the rat colon

Q3 · MEDICINE

Article

Author: Moha Ou Maati, H. ; Gil, V. ; Jiménez, M. ; Gallego, D. ; Peyronnet, R. ; Martínez-Cutillas, M. ; Heurteaux, C. ; Borsotto, M.

Purinergic and nitrergic neurotransmission predominantly mediate inhibitory neuromuscular transmission in the rat colon. We studied the sensitivity of both purinergic and nitrergic pathways to spadin, a TWIK-related potassium channel 1 (TREK1) inhibitor, apamin, a small-conductance calcium-activated potassium channel blocker and 1H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one (ODQ), a specific inhibitor of soluble guanylate cyclase. TREK1 expression was detected by RT-PCR in the rat colon. Patch-clamp experiments were performed on cells expressing hTREK1 channels. Spadin (1 μM) reduced currents 1) in basal conditions 2) activated by stretch, and 3) with arachidonic acid (AA; 10 μM). l-Methionine (1 mM) or l-cysteine (1 mM) did not modify currents activated by AA. Microelectrode and muscle bath studies were performed on rat colon samples. l-Methionine (2 mM), apamin (1 μM), ODQ (10 μM), and Nω-nitro-l-arginine (l-NNA; 1 mM) depolarized smooth muscle cells and increased motility. These effects were not observed with spadin (1 μM). Purinergic and nitrergic inhibitory junction potentials (IJP) were studied by incubating the tissue with l-NNA (1 mM) or MRS2500 (1 μM). Both purinergic and nitrergic IJP were unaffected by spadin. Apamin reduced both IJP with a different potency and maximal effect for each. ODQ concentration dependently abolished nitrergic IJP without affecting purinergic IJP. Similar effects were observed in hyperpolarizations induced by sodium nitroprusside (1 μM) and nitrergic relaxations induced by electrical stimulation. We propose a pharmacological approach to characterize the pathways and function of purinergic and nitrergic neurotransmission. Nitrergic neurotransmission, which is mediated by cyclic guanosine monophosphate, is insensitive to spadin, an effective TREK1 channel inhibitor. Both purinergic and nitrergic neurotransmission are inhibited by apamin but with different relative sensitivity.

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Indication	Highest Phase	Country/Location	Organization	Date
Ischemic stroke	Preclinical	China	Peking Union Medical College	05 Mar 2025

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