ML365
目录号 : GC36629
A TASK-1 potassium channel blocker
Cas No.:947914-18-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
ML-365 is a bis-amide TASK-1 potassium channel blocker (IC50 = 16 nM).1 It is selective for TASK-1 over TASK-3 channels in a QPatch assay (IC50 = 990 nM). It also acts as an antagonist of the metabotropic glutamate receptor mGluR5 (IC50 = 1.35 μM).2
1.Flaherty, D.P., Simpson, D.S., Miller, M., et al.Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffoldBioorg. Med. Chem. Lett.24(16)3968-3973(2014) 2.Zhou, Y., Rodriguez, A.L., Williams, R., et al.Synthesis and SAR of novel, non-MPEP chemotype mGluR5 NAMs identified by functional HTSBioorg. Med. Chem. Lett.19(23)6502-6506(2009)
| Cas No. | 947914-18-3 | SDF | |
| Canonical SMILES | O=C(C1=C(OC)C=CC=C1)NC2=CC=CC(NC(C3=CC=CC(C)=C3)=O)=C2 | ||
| 分子式 | C22H20N2O3 | 分子量 | 360.41 |
| 溶解度 | DMSO: ≥ 100 mg/mL (277.46 mM); Water: < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.7746 mL | 13.8731 mL | 27.7462 mL |
| 5 mM | 0.5549 mL | 2.7746 mL | 5.5492 mL |
| 10 mM | 0.2775 mL | 1.3873 mL | 2.7746 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
ML365 inhibits lipopolysaccharide-induced inflammatory responses via the NF-κB signaling pathway
Immunobiology 2022 May;227(3):152208.PMID:35405468DOI:10.1016/j.imbio.2022.152208.
ML365 is a selective inhibitor of the twik-related acid-sensitive potassium channel 1/two-pore domain channel subfamily k member 3 two-pore domain potassium channel. There are no functional studies of the relationship between ML365 and inhibition of inflammation. In this study, we evaluated the anti-inflammatory effect of ML365 on lipopolysaccharide (LPS)-induced inflammation and elucidated the possible mechanism. ML365 showed no cytotoxicity and did not induce apoptosis on RAW264.7 cells and inhibited nitric oxide production. ML365 suppressed the release of tumor necrosis factor-alpha, interleukin (IL)-6 and IL-1β measured using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction assays. LPS-induced activation and co-localization of NF-κB was inhibited by ML365 pre-treatment. ML365 inhibited the protein expression of Erk, p38 and Jnk. In vivo, ML365 appeared to prevent pathological damages in the LPS-induced endotoxin shock model. These findings suggest that ML365 inhibits LPS-induced inflammatory responses by regulating the NF-κB signaling pathway.
ML365 inhibits TWIK2 channel to block ATP-induced NLRP3 inflammasome
Acta Pharmacol Sin 2022 Apr;43(4):992-1000.PMID:34341510DOI:10.1038/s41401-021-00739-9.
Dysregulation of NLRP3 inflammasome results in uncontrolled inflammation, which participates in various chronic diseases. TWIK2 potassium channel mediates potassium efflux that has been reported to be an essential upstream mechanism for ATP-induced NLRP3 inflammasome activation. Thus, TWIK2 potassium channel could be a potential drug target for NLRP3-related inflammatory diseases. In the present study we investigated the effects of known K2P channel modulators on TWIK2 channel expressed in a heterologous system. In order to increase plasma membrane expression and thus TWIK2 currents, a mutant channel with three mutations (TWIK2I289A/L290A/Y308A) in the C-terminus was expressed in COS-7 cells. TWIK2 currents were assessed using whole-cell voltage-clamp recording. Among 6 known K2P channel modulators tested (DCPIB, quinine, fluoxetine, ML365, ML335, and TKDC), ML365 was the most potent TWIK2 channel blocker with an IC50 value of 4.07 ± 1.5 μM. Furthermore, ML365 selectively inhibited TWIK2 without affecting TWIK1 or THIK1 channels. We showed that ML365 (1, 5 μM) concentration-dependently inhibited ATP-induced NLRP3 inflammasome activation in LPS-primed murine BMDMs, whereas it did not affect nigericin-induced NLRP3, or non-canonical, AIM2 and NLRC4 inflammasomes activation. Knockdown of TWIK2 significantly impaired the inhibitory effect of ML365 on ATP-induced NLRP3 inflammasome activation. Moreover, we demonstrated that pre-administration of ML365 (1, 10, 25 mg/kg, ip) dose-dependently ameliorated LPS-induced endotoxic shock in mice. In a preliminary pharmacokinetic study conducted in rats, ML365 showed good absolute oral bioavailability with F value of 22.49%. In conclusion, ML365 provides a structural reference for future design of selective TWIK2 channel inhibitors in treating related inflammatory diseases.
A1899, PK-THPP, ML365, and Doxapram inhibit endogenous TASK channels and excite calcium signaling in carotid body type-1 cells
Physiol Rep 2018 Sep;6(19):e13876.PMID:30284397DOI:10.14814/phy2.13876.
Sensing of hypoxia and acidosis in arterial chemoreceptors is thought to be mediated through the inhibition of TASK and possibly other (e.g., BKCa ) potassium channels which leads to membrane depolarization, voltage-gated Ca-entry, and neurosecretion. Here, we investigate the effects of pharmacological inhibitors on TASK channel activity and [Ca2+ ]i -signaling in isolated neonatal rat type-1 cells. PK-THPP inhibited TASK channel activity in cell attached patches by up to 90% (at 400 nmol/L). A1899 inhibited TASK channel activity by 35% at 400 nmol/L. PK-THPP, A1899 and Ml 365 all evoked a rapid increase in type-1 cell [Ca2+ ]i . These [Ca2+ ]i responses were abolished in Ca2+ -free solution and greatly attenuated by Ni2+ (2 mM) suggesting that depolarization and voltage-gated Ca2+ -entry mediated the rise in [Ca2+ ]i. Doxapram (50 μmol/L), a respiratory stimulant, also inhibited type-1 cell TASK channel activity and increased [Ca2+ ]i. . We also tested the effects of combined inhibition of BKCa and TASK channels. TEA (5 mmol/L) slightly increased [Ca2+ ]i in the presence of PK-THPP and A1899. Paxilline (300 nM) and iberiotoxin (50 nmol/L) also slightly increased [Ca2+ ]i in the presence of A1899 but not in the presence of PK-THPP. In general [Ca2+ ]i responses to TASK inhibitors, alone or in combination with BKCa inhibitors, were smaller than the [Ca2+ ]i responses evoked by hypoxia. These data confirm that TASK channel inhibition is capable of evoking membrane depolarization and robust voltage-gated Ca2+ -entry but suggest that this, even with concomitant inhibition of BKCa channels, may be insufficient to account fully for the [Ca2+ ]i -response to hypoxia.
Spinal TASK-1 and TASK-3 modulate inflammatory and neuropathic pain
Eur J Pharmacol 2019 Nov 5;862:172631.PMID:31472119DOI:10.1016/j.ejphar.2019.172631.
This study assessed the participation of spinal TWIK-related acid-sensitive K+ channels 1 and 3 (TASK-1 and TASK-3) in inflammatory (formalin test) and neuropathic (spinal nerve ligation, SNL) pain in rats. Intrathecal pre-treatment (-10 min) with the TASK-1 blocker ML365 or TASK-3 blocker PK-THPP, but not vehicle, enhanced in a dose-dependent manner 1% formalin-induced acute and long-lasting secondary mechanical allodynia and mechanical hyperalgesia in rats. In contrast, intrathecal pre-treatment with terbinafine, an activator of TASK-3, reduced formalin-induced flinching and allodynia/hyperalgesia. Both blockers and terbinafine had similar effects on female and male rats. In addition, intrathecal injection of ML365 or PK-THPP blocked the terbinafine-induced antiallodynic effect in neuropathic rats, but they did not modify baseline withdrawal threshold in naïve or sham-operated rats. TASK-1 and TASK-3 mRNA and protein were expressed in L4 and L5 dorsal root ganglia (DRG) and dorsal and ventral spinal cord of naïve animals. Interestingly, formalin injection increased TASK-1 expression in ipsilateral L5 DRG, but not in the spinal cord. Moreover, formalin injection transiently enhanced TASK-3 expression in ipsilateral L5 DRG and dorsal spinal cord. In contrast, SNL down-regulated TASK-3 expression in the ipsilateral L4 and L5 DRG but not in dorsal or ventral spinal cord, while SNL did not modify TASK-1 expression at any tissue. The pharmacological and molecular results suggest that TASK-1 and TASK-3 have a relevant antinociceptive role in inflammatory and neuropathic pain.
Blockade of TASK-1 Channel Improves the Efficacy of Levetiracetam in Chronically Epileptic Rats
Biomedicines 2022 Mar 28;10(4):787.PMID:35453538DOI:10.3390/biomedicines10040787.
Tandem of P domains in a weak inwardly rectifying K+ channel (TWIK)-related acid sensitive K+-1 channel (TASK-1) is an outwardly rectifying K+ channel that acts in response to extracellular pH. TASK-1 is upregulated in the astrocytes (particularly in the CA1 region) of the hippocampi of patients with temporal lobe epilepsy and chronically epilepsy rats. Since levetiracetam (LEV) is an effective inhibitor for carbonic anhydrase, which has a pivotal role in buffering of extracellular pH, it is likely that the anti-epileptic action of LEV may be relevant to TASK-1 inhibition, which remains to be elusive. In the present study, we found that LEV diminished the upregulated TASK-1 expression in the CA1 astrocytes of responders (whose seizure activities were responsive to LEV), but not non-responders (whose seizure activities were not controlled by LEV) in chronically epileptic rats. ML365 (a selective TASK-1 inhibitor) only reduced seizure duration in LEV non-responders, concomitant with astroglial TASK-1 downregulation. Furthermore, ML365 co-treatment with LEV decreased the duration, frequency and severity of spontaneous seizures in non-responders to LEV. To the best of our knowledge, our findings suggest, for the first time, that the up-regulation of TASK-1 expression in CA1 astrocytes may be involved in refractory seizures in response to LEV. This may be a potential target to improve responsiveness to LEV.