Larixyl Acetate
(Synonyms: Larixol Acetate) 目录号 : GC49608A diterpenoid with TRPC6 inhibitory and analgesic activities
Cas No.:4608-49-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Larixyl acetate is a diterpenoid that has been found in Larix and has transient receptor potential canonical 6 (TRPC6) inhibitory and analgesic activities.1,2 It inhibits the activity of TRPC6 (IC50 = 0.58 µM) and is selective for TRPC6 over TRPC3 (IC50 = 6.83 µM), as well as over nine additional TRP channels at 10 µM.1 Intrathecal administration of larixyl acetate reduces mechanical and cold allodynia in a rat model of neuropathic pain induced by spared nerve injury (SNI).
1.Urban, N., Wang, L., Kwiek, S., et al.Identification and validation of larixyl acetate as a potent TRPC6 inhibitorMol. Pharmacol.89(1)197-213(2016) 2.Wang, J., Zhao, M., Jia, P., et al.The analgesic action of larixyl acetate, a potent TRPC6 inhibitor, in rat neuropathic pain model induced by spared nerve injuryJ. Neuroinflammation17(1)118(2020)
| Cas No. | 4608-49-5 | SDF | Download SDF |
| 别名 | Larixol Acetate | ||
| Canonical SMILES | C[C@]12[C@@](C(C)(CCC2)C)([H])[C@H](CC([C@@H]1CC[C@](C)(O)C=C)=C)OC(C)=O | ||
| 分子式 | C22H36O3 | 分子量 | 348.5 |
| 溶解度 | Chloroform: slightly soluble,Ethyl Acetate: slightly soluble | 储存条件 | Store at -20°C, protect from light |
| 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 | 2.8694 mL | 14.3472 mL | 28.6944 mL |
| 5 mM | 0.5739 mL | 2.8694 mL | 5.7389 mL |
| 10 mM | 0.2869 mL | 1.4347 mL | 2.8694 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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Identification and Validation of Larixyl Acetate as a Potent TRPC6 Inhibitor
Mol Pharmacol 2016 Jan;89(1):197-213.PMID:26500253DOI:10.1124/mol.115.100792.
Classical or canonical transient receptor potential 6 (TRPC6), a nonselective and Ca(2+)-permeable cation channel, mediates pathophysiological responses within pulmonary and renal diseases that are still poorly controlled by current medication. Thus, controlling TRPC6 activity may provide a promising and challenging pharmacological approach. Recently identified chemical entities have demonstrated that TRPC6 is pharmacologically targetable. However, isotype-selectivity with regard to its closest relative, TRPC3, is difficult to achieve. Reasoning that balsams, essential oils, or incense materials that are traditionally used for inhalation may contain biologic activities to block TRPC6 activity, we embarked on a natural compound strategy to identify new TRPC6-blocking chemical entities. Within several preparations of plant extracts, a strong TRPC6-inhibitory activity was found in conifer balsams. The biologic activity was associated with nonvolatile resins, but not with essential oils. Of various conifers, the larch balsam was unique in displaying a marked TRPC6-prevalent mode of action. By testing the main constituents of larch resin, we identified larixol and Larixyl Acetate as blockers of Ca(2+) entry and ionic currents through diacylglycerol- or receptor-activated recombinant TRPC6 channels, exhibiting approximately 12- and 5-fold selectivity compared with its closest relatives TRPC3 and TRPC7, respectively. No significant inhibition of more distantly related TRPV or TRPM channels was seen. The potent inhibition of recombinant TRPC6 by Larixyl Acetate (IC50 = 0.1-0.6 µM) was confirmed for native TRPC6-like [Ca(2+)]i signals in diacylglycerol-stimulated rat pulmonary artery smooth muscle cells. In isolated mouse lungs, larix-6-yl monoacetate (CAS 4608-49-5; Larixyl Acetate; 5 µM) prevented acute hypoxia-induced vasoconstriction. We conclude that larch-derived labdane-type diterpenes are TRPC6-selective inhibitors and may represent a starting point for pharmacological TRPC6 modulation within experimental therapies.
The analgesic action of Larixyl Acetate, a potent TRPC6 inhibitor, in rat neuropathic pain model induced by spared nerve injury
J Neuroinflammation 2020 Apr 16;17(1):118.PMID:32299452DOI:10.1186/s12974-020-01767-8.
Background: Neuropathic pain is a debilitating status that is insusceptible to the existing analgesics. It is important to explore the underlying pathophysiological changes and search for new pharmacological approaches. Transient receptor potential canonical 6 (TRPC6) is a mechanosensitive channel that is expressed by dorsal root ganglia and glial cells. It has been demonstrated that this channel in dorsal root ganglia plays essential roles in the formation of mechanical hyperalgesia in neuropathic pain. Recent pharmacological screening suggests that Larixyl Acetate (LA), a main constituent of larch resin, is able to selectively inhibit TRPC6 function. But whether LA is effective in treating neuropathic pain remains unknown. We investigated the efficacy of LA in rat neuropathic pain model, examined its effects on central neuroinflammation, and explored the possible molecular mechanisms by targeting the spinal dorsal horn. Methods: Spared nerve injury (SNI) was conducted in Sprague-Dawley rats. Mechanical hypersensitivity and cold allodynia before and after single and multiple i.t. applications of LA at the dose of 3, 10, and 30 μM were evaluated by von Frey filament and acetone tests, respectively. Western blot, immunohistochemical, and immunocytochemical stainings were employed to examine the level and expression feature of ionized calcium-binding adaptor molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), TRPC6, and phosphorylated p38 kinase. The changes of cytokine concentrations, including that of TNF-α, IL-1β, IL-6, and IL-10, were also assessed by multiplex analysis. TRPC6 antisense strategy was finally adopted to investigate the action mechanisms of LA. Results: Single application of LA on day 5 post injury caused dose-dependent inhibition of mechanical allodynia with the ED50 value of 13.43 μM. Multiple applications of LA at 30 μM not only enhanced the analgesic efficacy but also elongated the effective duration without obvious influences on animal locomotor activities. Single and multiple administrations of LA at 30 μM played similar but weaker inhibitory effects on cold allodynia. In addition to behavioral improvements, multiple applications of LA for 6 days dose-dependently inhibited the upregulation of Iba-1, TNF-α, IL-1β, and IL-6, whereas had no obvious effects on the levels of GFAP and IL-10. Combined Western blot and immunostaining assays revealed that the expression of TRPC6 was significantly increased in both spinal dorsal horn after nerve injury and the cultured microglia challenged by LPS, which was however suppressed by the addition of LA at 30 μM or 10 μM, respectively. Further knockdown of TRPC6 with antisense oligodeoxynucleotide produced prominent analgesic effects in rats with SNI, accompanied by the reduced phosphorylation level of p38 in the microglia. Conclusions: These data demonstrate that i.t. applied LA exhibits analgesic and anti-inflammatory action in neuropathic pain. The action of LA involves the suppression of TRPC6 and p38 signaling in the microglia. LA may be thus a promising pharmacological candidate for the treatment of intractable chronic pain.
The TRPC6 inhibitor, Larixyl Acetate, is effective in protecting against traumatic brain injury-induced systemic endothelial dysfunction
J Neuroinflammation 2019 Jan 31;16(1):21.PMID:30704505DOI:10.1186/s12974-019-1407-6.
Background: The incidence of traumatic brain injuries (TBIs) is on the rise in the USA. Concussions, or mild TBIs without skull fracture, account for about 75% of all TBIs. Mild TBIs (mTBIs) lead to memory and cognitive deficits, headaches, intraocular pressure rises, axonal degeneration, neuroinflammation, and an array of cerebrovascular dysfunctions, including increased vascular permeability and decreased cerebral blood flow. It has been recently reported that besides vascular dysfunction in the cerebral circulation, mTBI may also cause a significant impairment of endothelial function in the systemic circulation, at least within mesenteric microvessels. In this study, we investigated whether mTBI affects endothelial function in aortas and determined the contribution of transient receptor potential canonical (TRPC) channels to modulating mTBI-associated endothelial dysfunction. Methods: We used a model of closed-head mTBI in C57BL/6, 129S, 129S-C57BL/6-F2 mice, and 129S-TRPC1 and 129S-C57BL/6-TRPC6 knockout mice to determine the effect of mTBI on endothelial function in mouse aortas employing ex vivo isometric tension measurements. Aortic tissue was also analyzed using immunofluorescence and qRT-PCR for TRPC6 expression following mTBI. Results: We show that in various strains of mice, mTBI induces a pronounced and long-lasting endothelial dysfunction in the aorta. Ablation of TRPC6 protects mice from mTBI-associated aortic endothelial dysfunction, while TRPC1 ablation does not impact brain injury-induced endothelial impairment in the aorta. Consistent with a role of TRPC6 activation following mTBI, we observed improved endothelial function in wild type control mice subjected to mTBI following 7-day in vivo treatment with Larixyl Acetate, an inhibitor of TRPC6 channels. Conversely, in vitro treatment with the pro-inflammatory endotoxin lipopolysaccharide, which activates endothelial TRPC6 in a Toll-like receptor type 4 (TLR4)-dependent manner, worsened aortic endothelial dysfunction in wild type mice. Lipopolysaccharide treatment in vitro failed to elicit endothelial dysfunction in TRPC6 knockout mice. No change in endothelial TRPC6 expression was observed 7 days following TBI. Conclusions: These data suggest that TRPC6 activation may be critical for inducing endothelial dysfunction following closed-head mTBI and that pharmacological inhibition of the channel may be a feasible therapeutic strategy for preventing mTBI-associated systemic endothelial dysfunction.
Reducing copper use in the environment: the use of larixol and Larixyl Acetate to treat downy mildew caused by Plasmopara viticola in viticulture
Pest Manag Sci 2018 Feb;74(2):477-488.PMID:28905481DOI:10.1002/ps.4733.
Background: Plant extracts might provide sustainable alternatives to copper fungicides, which are still widely used despite their unfavourable ecotoxicological profile. Larch bark extract and its constituents, Larixyl Acetate and larixol, have been shown to be effective against grapevine downy mildew (Plasmopara viticola) under semi-controlled conditions. The aim of this study was to reduce the gap between innovation and the registration of a marketable product, namely to develop scalable extraction processes and to evaluate and optimise the performance of larch extracts under different conditions. Results: Toxicologically and technically acceptable solvents like ethanol were used to extract the active compounds Larixyl Acetate and larixol from bark in sufficient amounts and their combined concentration could be increased by up to 39% by purification steps. The combined concentration of Larixyl Acetate and larixol from larch turpentine could be increased by up to 66%. The Minimal Inhibitory Concentration (MIC100 ) against P. viticola in vitro (6-23 µg mL-1 ) and the Effective Concentration (EC50 ) in planta under semi-controlled conditions (0.2-0.4 mg mL-1 ) were promising compared with other plant extracts. In vineyards, efficacies of larch extracts reached up to 68% in a stand-alone strategy and 84% in low-copper strategies. Conclusion: Larch extracts represent valid candidates for copper reduction in organic vineyards, and their development into a sustainable plant protection product might be feasible. © 2017 Society of Chemical Industry.
Pharmacological and genetic inhibition of TRPC6-induced gene transcription
Eur J Pharmacol 2020 Nov 5;886:173357.PMID:32758574DOI:10.1016/j.ejphar.2020.173357.
Transient receptor potential canonical-6 (TRPC6) channels are non-selective cation channels that can be activated by hyperforin, a constituent of Hypericum perforatum. TRPC6 activation has been linked to a variety of biological functions and pathologies, including focal segmental glomerulosclerosis and the development of various tumor entities. Thus, TRPC6 is an interesting drug target, and a specific pharmacological inhibitor would be very valuable for both basic research and therapy of TRPC6-mediated human pathologies. Here, we assessed the biological activity of various TRP channel inhibitors on hyperforin-stimulated TRPC6 channel signaling. Hyperforin stimulates the activity of the transcription factor AP-1 via TRPC6. Expression experiments involving a TRPC6-specific small hairpin RNA confirmed that hyperforin-induced gene transcription requires TRPC6. Cellular AP-1 activity was measured to assess which compound interrupted the TRPC6-induced intracellular signaling cascade. The results show that the compounds 2-APB, clotrimazole, BCTC, TC-I 2014, SAR 7334, and Larixyl Acetate blocked TRPC6-mediated activation of AP-1. In contrast, the TRPM8-specific inhibitor RQ-00203078 did not inhibit TRPC6-mediated signaling. 2-APB, clotrimazole, BCTC, and TC-I 2014 are broad-spectrum Ca2+ channel inhibitors, while SAR 7334 and Larixyl Acetate have been proposed to function as rather TRPC6-specific inhibitors. In this study it is shown that both compounds, in addition to inhibiting TRPC6-induced signaling, completely abolished pregnenolone sulfate-mediated signaling via TRPM3 channels. Thus, SAR 7334 and Larixyl Acetate are not TRPC6-specific inhibitors.