IAA-94
(Synonyms: R-(+)-甲基吲唑酮,R(+)-IAA 94) 目录号 : GC15308
IAA-94 (Indanyloxyacetic acid-94) 是一种细胞内氯离子通道阻滞剂。
Cas No.:54197-31-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
murine microglial cell line BV-2, Primary microglial cell |
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Preparation Method |
Flow cytometry was used to measure BV-2 cell uptake of fluorescent beads after stimulation with Aβ25-35, the active fragment of Aβ, and Aβ35-25, the reverse, inactive form. Cells were treated with aggregated Aβ25-35 (50 µM) for 30 min, 90 min, and 3 hr in the presence or not of the CLIC-1 inhibitor IAA-94 and with Aβ35-25 (50 µM) for 3 hr. Treatments were performed on cells in suspension at 37°C; afterward, cells were washed with medium. |
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Reaction Conditions |
30 µM for 3 h |
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Applications |
Primary microglia showed a phagocytic ability that remained substantially unmodified after Aβ treatment. Treatment with IAA-94 did not modify the phagocytic ability of these cells. |
| Animal experiment [2]: | |
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Animal models |
Male CD-1 mice weighing 25-30 g |
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Preparation Method |
Groups of mice were treated i.t. with a selective δ-opioid receptor agonist [D-Ala2]deltorphin II (10 µg) in 10% 2-hydroxypropyl-β-cyclodextrin/saline solution (5 µl), and the antinociception induced by [D-Ala2]deltorphin II was measured for 1 h after the treatment. In order to ascertain the role of Ca2+-activated Cl- channels in the expression of δ-opioid receptor-mediated antinociception, a selective Ca2+-activated Cl- channel blocker IAA-94(2% Tween 20/saline solution, 1, 3, 10 µg in 5 µl) was pretreated i.t. 10 min prior to the [D-Ala2]deltorphin II injection. |
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Dosage form |
1, 3, 10 µg in 5 µl, i.t. |
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Applications |
Mice injected [D-Ala2]deltorphin II showed a marked antinociception (peak effect: 79.5±11.1% MPE). The antinociception induced by [D-Ala2]deltorphin II was attenuated by i.t.-pretreatment with IAA-94 in a dose-dependent manner, and the peak effect was significantly reduced to 44.8±10.0% MPE by 10 µg of IAA-94. |
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References: [1]: Paradisi S, Matteucci A, Fabrizi C, et al. Blockade of chloride intracellular ion channel 1 stimulates Aβ phagocytosis[J]. Journal of neuroscience research, 2008, 86(11): 2488-2498. |
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IAA-94 (Indanyloxyacetic acid-94) is an intracellular chloride channel blocker [1]. IAA-94 inhibited CLIC-1-dependent chloride permeability with an apparent IC50 of 8.6 μM [2]. IAA-94 depressed the K+-induced force with an IC50 of 17.0 ± 1.2 μM [3].
In cells treated with IAA-94 (30 μM) with respect to control, the amount of intracellular Aβ1-42 phagocytosis was remarkably increased after 24 hr of incubation [4]. Inhibition of Cl- channels with pan-chloride channel blocker IAA-94 (50 μM) abolished the protection induced by 200 nM CsA pre-treatment in cardiomyocytes [5]. The anion channel blocker IAA-94 (200 μM) significantly blocked glutamate and taurine release against Astrocytes in hypotonic solution [6].
IAA-94 was shown to abrogate cardioprotection mediated by IPC and cyclosporin A (CsA) [7]. Adult male rat hearts were subjected to the left coronary artery occlusion for 45min followed by 3h of reperfusion. A single intravenous bolus of phosphate buffered saline (PBS) (control) or IAA-94 (20mg/kg body weight) was administered 5min before reperfusion. The infarct size (IS) was significantly higher in the IAA-94-treated group compared to control; the ratio of IS to area at risk was 58.1±7% in IAA-94 vs. 33.5±6% in control in this rat model [1].
References:
[1]. Ponnalagu D, Hussain A T, Thanawala R, et al. Chloride channel blocker IAA-94 increases myocardial infarction by reducing calcium retention capacity of the cardiac mitochondria[J]. Life sciences, 2019, 235: 116841.
[2]. Tulk B M, Schlesinger P H, Kapadia S A, et al. CLIC-1 functions as a chloride channel when expressed and purified from bacteria[J]. Journal of Biological Chemistry, 2000, 275(35): 26986-26993.
[3]. Doughty J M, Miller A L, Langton P D. Non‐specificity of chloride channel blockers in rat cerebral arteries: block of the L‐type calcium channel[J]. The Journal of physiology, 1998, 507(2): 433-439.
[4]. Paradisi S, Matteucci A, Fabrizi C, et al. Blockade of chloride intracellular ion channel 1 stimulates Aβ phagocytosis[J]. Journal of neuroscience research, 2008, 86(11): 2488-2498.
[5]. Diaz R J, Fernandes K, Lytvyn Y, et al. Enhanced cell-volume regulation in cyclosporin A cardioprotection[J]. Cardiovascular research, 2013, 98(3): 411-419.
[6]. Ye Z C, Oberheim N, Kettenmann H, et al. Pharmacological “cross‐inhibition” of connexin hemichannels and swelling activated anion channels[J]. Glia, 2009, 57(3): 258-269.
[7]. Diaz R J, Losito V A, Mao G D, et al. Chloride channel inhibition blocks the protection of ischemic preconditioning and hypo-osmotic stress in rabbit ventricular myocardium[J]. Circulation research, 1999, 84(7): 763-775.
IAA-94 (Indanyloxyacetic acid-94) 是一种细胞内氯离子通道阻滞剂[1]。 IAA-94 抑制 CLIC-1 依赖性氯离子渗透性，表观 IC50 为 8.6 μM [2]。 IAA-94 抑制 K+- 诱导力，IC50 为 17.0 ± 1.2 μM [3]。
相对于对照，在用 IAA-94 (30 μM) 处理的细胞中，细胞内 Aβ1-42 吞噬量在孵育 24 小时后显着增加 [4]。用泛氯离子通道阻滞剂 IAA-94 (50 μM) 抑制 Cl- 通道消除了 200 nM CsA 预处理对心肌细胞诱导的保护作用[5]。阴离子通道阻滞剂 IAA-94 (200 μM) 显着阻断谷氨酸和牛磺酸在低渗溶液中对星形胶质细胞的释放[6]。
IAA-94 被证明可以消除由 IPC 和环孢菌素 A (CsA) [7] 介导的心脏保护作用。对成年雄性大鼠心脏进行左冠状动脉闭塞 45 分钟，然后再灌注 3 小时。再灌注前 5 分钟给予单次静脉推注的磷酸盐缓冲盐水 (PBS)（对照）或 IAA-94（20mg/kg 体重）。与对照组相比，IAA-94 治疗组的梗塞面积 (IS) 明显更高；在该大鼠模型中，IS 与风险面积的比率在 IAA-94 中为 58.1±7%，而在对照组中为 33.5±6%[1]。
| Cas No. | 54197-31-8 | SDF | |
| 别名 | R-(+)-甲基吲唑酮,R(+)-IAA 94 | ||
| 化学名 | 2-[[(2R)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl]oxy]-acetic acid | ||
| Canonical SMILES | ClC1=C(C([C@](C2CCCC2)(C)C3)=O)C3=CC(OCC(O)=O)=C1Cl | ||
| 分子式 | C17H18Cl2O4 | 分子量 | 357.2 |
| 溶解度 | ≤15mg/ml in ethanol;15mg/ml in DMSO;15mg/ml in dimethyl formamide | 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 | 2.7996 mL | 13.9978 mL | 27.9955 mL |
| 5 mM | 0.5599 mL | 2.7996 mL | 5.5991 mL |
| 10 mM | 0.28 mL | 1.3998 mL | 2.7996 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。
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Chloride channel blocker IAA-94 increases myocardial infarction by reducing calcium retention capacity of the cardiac mitochondria
Life Sci2019 Oct 15;235:116841.PMID: 31494173DOI: 10.1016/j.lfs.2019.116841
Indanyloxyacetic acid-94 (IAA-94), an intracellular chloride channel blocker, is shown to ablate cardioprotection rendered by ischemic preconditioning (IPC), N (6)-2-(4-aminophenyl) ethyladenosine or the PKC activator phorbol 12-myristate 13-acetate and cyclosporin A (CsA) in both ex-vivo and in-vivo ischemia-reperfusion (IR) injury. Thus signifying the role of the IAA-94 sensitive chloride channels in mediating cardio-protection upon IR injury. Although IAA-94 sensitive chloride currents are recorded in cardiac mitoplast, there is still a lack of understanding of the mechanism by which IAA-94 increases myocardial infarction (MI) by IR injury. Mitochondria are the key arbitrators of cell life and death pathways. Both oxidative stress and calcium overload in the mitochondria, elicit pathways resulting in the opening of mitochondrial permeability transition pore (mPTP) leading to cell death. Therefore, in this study we explored the role of IAA-94 in MI and in maintaining calcium retention capacity (CRC) of cardiac mitochondria after IR. IAA-94 inhibited the CRC of the isolated cardiac mitochondria in a concentration-dependent manner as measured spectrofluorimetrically using calcium green-5 N. Interestingly, IAA-94 did not change the mitochondrial membrane potential. Further, CsA a blocker of mPTP opening could not override the effect of IAA-94. We also showed for the first time that IAA-94 perfusion after ischemic event augments MI by reducing the CRC of mitochondria. To conclude, our results demonstrate that the mechanism of IAA-94 mediated cardio-deleterious effects is via modulating the mitochondria CRC, thereby playing a role in mPTP opening. These findings highlight new pharmacological targets, which can mediate cardioprotection from IR injury.
The bizarre pharmacology of the ATP release channel pannexin1
Neuropharmacology2013 Dec;75:583-93.PMID: 23499662DOI: 10.1016/j.neuropharm.2013.02.019
Pannexins were originally thought to represent a second and redundant family of gap junction proteins in addition to the well characterized connexins. However, it is now evident that pannexins function as unapposed membrane channels and the major role of Panx1 is that of an ATP release channel. Despite the contrasting functional roles, connexins, innexins and pannexins share pharmacological properties. Most gap junction blockers also attenuate the function of Panx1, including carbenoxolone, mefloquine and flufenamic acid. However, in contrast to connexin based gap junction channels, Panx1 channel activity can be attenuated by several groups of drugs hitherto considered very specific for other proteins. The drugs affecting Panx1 channels include several transport inhibitors, chloride channel blockers, mitochondrial inhibitors, P2X7 receptor ligands, inflammasome inhibitors and malaria drugs. These observations indicate that Panx1 may play an extended role in a wider spectrum of physiological functions. Alternatively, Panx1 may share structural domains with other proteins, not readily revealed by sequence alignments. This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'.
Epithelial chloride channel. Development of inhibitory ligands
J Gen Physiol1987 Dec;90(6):779-98.PMID: 2450168DOI: 10.1085/jgp.90.6.779
Chloride channels are present in the majority of epithelial cells, where they mediate absorption or secretion of NaCl. Although the absorptive and secretory channels are well characterized in terms of their electrophysiological behavior, there is a lack of pharmacological ligands that can aid us in further functional and eventually molecular characterization. To obtain such ligands, we prepared membrane vesicles from bovine kidney cortex and apical membrane vesicles from trachea and found that they contain a chloride transport process that is electrically conductive. This conductance was reduced by preincubating the vesicles in media containing ATP or ATP-gamma-S, but not beta-methylene ATP, which suggests that the membranes contain a kinase that can close the channels. We then screened compounds derived from three classes: indanyloxyacetic acid (IAA), anthranilic acid (AA), and ethacrynic acid. We identified potent inhibitors from the IAA and the AA series. We tritiated IAA-94 and measured binding of this ligand to the kidney cortex membrane vesicles and found a high-affinity binding site whose dissociation constant (0.6 microM) was similar to the inhibition constant (1 microM). There was a good correlation between the inhibitory potency of several IAA derivatives and their efficacy in displacing [3H]IAA-94 from its binding site. Further, other chloride channel inhibitors, including AA derivatives, ethacrynic acid, bumetanide, and DIDS, also displaced the ligand from its binding site. A similar conductance was found in apical membrane vesicles from bovine trachea that was also inhibited by IAA-94 and AA-130B, but the inhibitory effects of these compounds were weaker than their effects on the renal cortex channel. The two drugs were also less potent in displacing [3H]IAA-94 from the tracheal binding site.
Chloride channel blockade attenuates the effect of angiotensin II on tubuloglomerular feedback in WKY but not spontaneously hypertensive rats
Kidney Blood Press Res2004;27(1):35-42.PMID: 14679313DOI: 10.1159/000075621
Recent studies have shown that calcium-dependent chloride channels may play a crucial role in the modulation of the vascular effects of angiotensin II (ANG II). Thus, alterations in the function of these channels may be responsible for the enhanced renal vasoconstrictor and tubuloglomerular feedback (TGF) response to ANG II in spontaneously hypertensive rats (SHR). We investigated the effect of the calcium-dependent chloride channel blocker IAA-94 on renal hemodynamics and TGF responses. The renal interstitium was perfused with control solution, with ANG II, and with both ANG II and IAA-94. In Wistar Kyoto rats (WKY), perfusion with ANG II significantly increased renal vascular resistance (RVR), but the effect was significantly attenuated by perfusion with ANG II/IAA-94. In SHR, ANG II caused a significant elevation of RVR that was not altered by the simultaneous infusion of IAA-94. Proximal tubular stop flow pressure (P(sf)) was monitored during perfusion of peritubular capillaries with control solution, and subsequently with IAA-94, ANG II or both ANG II and IAA-94. TGF response magnitude of WKY rats was significantly augmented with ANG II, and this effect was suppressed by perfusion with ANG II /IAA-94. However, in SHR peritubular perfusion with ANG II/IAA-94 did not suppress the TGF response. We conclude that chloride channels susceptible to IAA-94 may play a significant role in modulating the effects of ANG II on renal hemodynamics, and that this modulation is absent in SHR.
Colonic Cl channel blockade by three classes of compounds
Am J Physiol1991 Jul;261(1 Pt 1):C51-63.PMID: 1713412DOI: 10.1152/ajpcell.1991.261.1.C51
We compared the potency and inhibitory actions of three different classes of organic acids on a Cl channel derived from colonic enterocyte plasma membrane vesicles. Chloride channels were incorporated into planar lipid bilayer membranes to examine the effects of the anthranilic acids, diphenylamine 2-carboxylic acid (DPC) and 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), the indanyl alkanoic acids, 2-[(2-cyclopentyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-1H-inden -5-yl)oxy] acetic acid (IAA-94) and its stereoenantiomer IAA-95, and the disulfonic stilbene, 4,4'-dinitro-stilbene-2,2'-disulfonic acid (DNDS). Except for DNDS, each of the blockers was equipotent from both the outer membrane and the cytoplasmic side of the channel protein. The potency order from the outmembrane side was DNDS greater than IAA-94 = IAA-95 greater than NPPB much greater than DPC. In contrast, the potency order from the cytoplasmic side was IAA-94 = IAA-95 greater than NPPB greater than DNDS much greater than DPC. DPC and NPPB caused a concentration-dependent decrease in the single-channel conductance (fast block). DNDS, IAA-94, and IAA-95 caused a flickery-type block and a concentration-dependent decrease in open-channel probability. Kinetic analysis revealed that blockade could be explained by a linear closed-opened-blocked kinetic scheme. Similarities in the electrostatic potential maps of these open-channel blockers suggest they may bind to a single shared binding site within the channel protein.