A 967079 - CAS 1170613-55-4
Catalog number: B0084-359603
Category: Inhibitor
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TRP Channel
A 967079 is a selective TRPA1 channel blocker (IC50 = 67 and 289 nM at human and rat TRPA1 receptors, respectively) with 1000-fold selectivity for TRPA1 over other TRP channels. A 967079 was shown to have analgesic effects in a rat osteoarthritic pain model.
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B0084-359603 100 mg $399 In stock
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Brife Description:
TRPA1 channel blocker
≥98% by HPLC
(1E,3E)-1-(4-Fluorophenyl)-2-methyl-1-pentene-3-one oxime; 1-(4-Fluorophenyl)-2-methyl-1-penten-3-one oxime
Canonical SMILES:
1.Sites Contributing to TRPA1 Activation by the Anesthetic Propofol Identified by Photoaffinity Labeling.
Woll KA;Skinner KA;Gianti E;Bhanu NV;Garcia BA;Carnevale V;Eckenhoff RG;Gaudet R Biophys J. 2017 Nov 21;113(10):2168-2172. doi: 10.1016/j.bpj.2017.08.040. Epub 2017 Sep 19.
In addition to inducing anesthesia, propofol activates a key component of the pain pathway, the transient receptor potential ankyrin 1 ion channel (TRPA1). Recent mutagenesis studies suggested a potential activation site within the transmembrane domain, near the A-967079 cavity. However, mutagenesis cannot distinguish between protein-based and ligand-based mechanisms, nor can this site explain the complex modulation by propofol. Thus more direct approaches are required to reveal potentially druggable binding sites. Here we apply photoaffinity labeling using a propofol derivative, meta-azipropofol, for direct identification of binding sites in mouse TRPA1. We confirm that meta-azipropofol activates TRPA1 like the parent anesthetic, and identify two photolabeled residues (V954 and E969) in the S6 helix. In combination with docking to closed and open state models of TRPA1, photoaffinity labeling suggested that the A-967079 cavity is a positive modulatory site for propofol. Further, the photoaffinity labeling of E969 indicated pore block as a likely mechanism for propofol inhibition at high concentrations. The direct identification of drug-binding sites clarifies the molecular mechanisms of important TRPA1 agonists, and will facilitate drug design efforts to modulate TRPA1.
2.Methylglyoxal mediates streptozotocin-induced diabetic neuropathic pain via activation of the peripheral TRPA1 and Nav1.8 channels.
Huang Q;Chen Y;Gong N;Wang YX Metabolism. 2016 Apr;65(4):463-74. doi: 10.1016/j.metabol.2015.12.002. Epub 2015 Dec 17.
OBJECTIVE: ;Methylglyoxal is known to be associated with the development of nephropathy, retinopathy, and other complications in diabetes. The present study tested the hypothesis that endogenously increased levels of methylglyoxal in diabetes are causally associated with the induction of neuropathic pain.;MATERIALS AND METHODS: ;Streptozotocin- and methylglyoxal-induced pain models were established in rats, and the anti-nociceptive effects of the methylglyoxal scavenging agents, selective transient receptor potential channel ankyrin 1 (TRPA1) antagonist, and Nav1.8 antagonist were tested.;RESULTS: ;Systemic injection of streptozotocin in rats induced a prolonged increase in plasma methylglyoxal by approximately 60%, which was correlated with the progressive development of mechanical allodynia and thermal hyperalgesia. Local subcutaneous injection of methylglyoxal into the hindpaw produced dose-dependent and biphasic flinching nociceptive responses, which resembled formaldehyde (formalin)-induced nociception. The local methylglyoxal nociception was significantly blocked by co-injection into the hindpaw of the selective transient receptor potential channel ankyrin 1 (TRPA1) antagonist, A967079, and the Nav1.
3.Proton-gated Ca(2+)-permeable TRP channels damage myelin in conditions mimicking ischaemia.
Hamilton NB;Kolodziejczyk K;Kougioumtzidou E;Attwell D Nature. 2016 Jan 28;529(7587):523-7. doi: 10.1038/nature16519. Epub 2016 Jan 13.
The myelin sheaths wrapped around axons by oligodendrocytes are crucial for brain function. In ischaemia myelin is damaged in a Ca(2+)-dependent manner, abolishing action potential propagation. This has been attributed to glutamate release activating Ca(2+)-permeable N-methyl-D-aspartate (NMDA) receptors. Surprisingly, we now show that NMDA does not raise the intracellular Ca(2+) concentration ([Ca(2+)]i) in mature oligodendrocytes and that, although ischaemia evokes a glutamate-triggered membrane current, this is generated by a rise of extracellular [K(+)] and decrease of membrane K(+) conductance. Nevertheless, ischaemia raises oligodendrocyte [Ca(2+)]i, [Mg(2+)]i and [H(+)]i, and buffering intracellular pH reduces the [Ca(2+)]i and [Mg(2+)]i increases, showing that these are evoked by the rise of [H(+)]i. The H(+)-gated [Ca(2+)]i elevation is mediated by channels with characteristics of TRPA1, being inhibited by ruthenium red, isopentenyl pyrophosphate, HC-030031, A967079 or TRPA1 knockout. TRPA1 block reduces myelin damage in ischaemia. These data suggest that TRPA1-containing ion channels could be a therapeutic target in white matter ischaemia.
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CAS 1170613-55-4 A 967079

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