TTA-A2
(Synonyms: 2(4-环丙基苯基)-N[(1R)-1-[5-(2,2,2-三氟乙氧基)吡啶-2-基]乙基]乙酰胺) 目录号 : GC61358
TTA-A2是一种强效、选择性和口服活性的T型电压门控钙通道(calcium channel)拮抗剂，可减少孕烷X受体(PXR)的激活。TTA-A2对Cav3.1(a1G)和Cav3.2(a1H)通道在-80mV和-100mV保持电位上具有同样的作用，IC50值分别为89nM和92nM。TTA-A2可用于多种人类神经系统疾病的研究，包括睡眠障碍和癫痫。
Cas No.:953778-63-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
TTA-A2 is a potent, selective and orally active t-type voltage gated calcium channel antagonist with reduced pregnane X receptor (PXR) activation. TTA-A2 is equally potent against the Cav3.1 (a1G) and Cav3.2 (a1H) channels with IC50 values of 89 nM and 92 nM, respectively, at -80 and -100 mV holding potentials. TTA-A2 can be used for the research of a variety of human neurological diseases, including sleep disorders and epilepsy[1][2].
TTA-A2 exhibits a state-dependent inhibition of α1I with potencies of 98 nM and 3.7 μM at membrane holding potentials of -80 and -100 mV, respectively in astandard voltage-clamp electrophysiology assay. It also exhibits excellent selectivity against the Cav1.2 (L-type), Cav2.1 (P/Q-type), Cav2.2 (N-type), and Cav2.3 (R-type) channels which all had IC50 values of >30 μM at 80 mV[1].TTA-A2 exhibits high affinity in the α1I binding assay with a Ki of 1.2 nM and has excellent selectivity over the hERG potassium channel and L-type calcium channel (both IC50>10 μM)[1].
TTA-A2 (oral gavage; 3 mg/kg; single dose) produces significant changes in sleep architecture in rats. A reduction in active wake soon after dosing with a concurrent increase in delta sleep and decrease in REM sleep. Additionally, these effects persists for up to 4 h post-dose in rats[1].TTA-A2 (oral gavage; 10 mg/kg; once daily; 5 days) shows selective effect on recurrent thalamocortical network activity, it suppresses active wake and promotes slow-wave sleep in wild-type mice but not in mice lacking both Cav3.1 and Cav3.3[2]. Animal Model: Wild-type and double Cav3.1/Cav3.3 knockout C57BL6/Sv129 background mices[2]
[1]. Thomas S Reger, et al.Pyridyl amides as potent inhibitors of T-type [2]. Richard L Kraus, et al.In vitro characterization of T-type calcium channel antagonist TTA-A2 and in vivo effects on arousal in mice. J Pharmacol Exp Ther. 2010 Nov;335(2):409-17.
| Cas No. | 953778-63-7 | SDF | |
| 别名 | 2(4-环丙基苯基)-N[(1R)-1-[5-(2,2,2-三氟乙氧基)吡啶-2-基]乙基]乙酰胺 | ||
| Canonical SMILES | O=C(N[C@@H](C1=NC=C(OCC(F)(F)F)C=C1)C)CC2=CC=C(C3CC3)C=C2 | ||
| 分子式 | C20H21F3N2O2 | 分子量 | 378.39 |
| 溶解度 | DMSO : 100 mg/mL (264.28 mM; Need ultrasonic) | 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。 | ||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6428 mL | 13.2139 mL | 26.4278 mL |
| 5 mM | 0.5286 mL | 2.6428 mL | 5.2856 mL |
| 10 mM | 0.2643 mL | 1.3214 mL | 2.6428 mL |
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动物平均体重 | g | |
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动物数量 | 只 |
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Antagonistic interaction between TTA-A2 and paclitaxel for anti-cancer effects by complex formation with T-type calcium channel
J Biomol Struct Dyn 2022 Apr;40(6):2395-2406.PMID:33103598DOI:10.1080/07391102.2020.1839558.
Studies have shown that in cancer cells, there is an increased T-type calcium channel (TTCC) expression compared to healthy cells. Therefore, the studies targeting TTCC for cancer therapy have shown many positive outcomes. Here, we have used TTA-A2- a potent TTCC inhibitor as a test drug, and paclitaxel (PTX)- a tubule-binding anti-cancer agent as a positive control. Blocking TTCC has shown to overcome resistance in cancer cells towards anti-cancer drugs by reducing calcium influx, and some studies have shown that PTX treatment also reduces the intracellular calcium signaling in cells. So, there is a possibility that PTX might be interacting with calcium channels. Since, drug-drug interaction can cause severe side-effects, or alter the actions of each other; we aim to study the interactions among TTA-A2, PTX, and TTCC. In this study, we have used computational analysis to test the binding of TTA-A2 and PTX with TTCC. To confirm the in-silico result, we further tested these drugs in a 3D spheroid model of A549, a lung adenocarcinoma cell line. The in-silico result showed that both the drugs, TTA-A2 and PTX, could interact at the same site of TTCC to form a higher stable complex as compared to the TTCC-native. The in vitro result showed the antagonistic interaction between the drugs when they are used at the same time. By using the sequential treatment, the spheroids were sensitized by TTA-A2, before treating with PTX. The result indicated that sequential treatment could help to overcome the antagonistic interaction between the two drugs. Communicated by Ramaswamy H. Sarma.
Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets
Front Pain Res (Lausanne) 2021 Dec 13;2:750583.PMID:35295464DOI:10.3389/fpain.2021.750583.
The persistence of increased excitability and spontaneous activity in injured peripheral neurons is imperative for the development and persistence of many forms of neuropathic pain. This aberrant activity involves increased activity and/or expression of voltage-gated Na+ and Ca2+ channels and hyperpolarization activated cyclic nucleotide gated (HCN) channels as well as decreased function of K+ channels. Because they display limited central side effects, peripherally restricted Na+ and Ca2+ channel blockers and K+ channel activators offer potential therapeutic approaches to pain management. This review outlines the current status and future therapeutic promise of peripherally acting channel modulators. Selective blockers of Nav1.3, Nav1.7, Nav1.8, Cav3.2, and HCN2 and activators of Kv7.2 abrogate signs of neuropathic pain in animal models. Unfortunately, their performance in the clinic has been disappointing; some substances fail to meet therapeutic end points whereas others produce dose-limiting side effects. Despite this, peripheral voltage-gated cation channels retain their promise as therapeutic targets. The way forward may include (i) further structural refinement of K+ channel activators such as retigabine and ASP0819 to improve selectivity and limit toxicity; use or modification of Na+ channel blockers such as vixotrigine, PF-05089771, A803467, PF-01247324, VX-150 or arachnid toxins such as Tap1a; the use of Ca2+ channel blockers such as TTA-P2, TTA-A2, Z 944, ACT709478, and CNCB-2; (ii) improving methods for assessing "pain" as opposed to nociception in rodent models; (iii) recognizing sex differences in pain etiology; (iv) tailoring of therapeutic approaches to meet the symptoms and etiology of pain in individual patients via quantitative sensory testing and other personalized medicine approaches; (v) targeting genetic and biochemical mechanisms controlling channel expression using anti-NGF antibodies such as tanezumab or re-purposed drugs such as vorinostat, a histone methyltransferase inhibitor used in the management of T-cell lymphoma, or cercosporamide a MNK 1/2 inhibitor used in treatment of rheumatoid arthritis; (vi) combination therapy using drugs that are selective for different channel types or regulatory processes; (vii) directing preclinical validation work toward the use of human or human-derived tissue samples; and (viii) application of molecular biological approaches such as clustered regularly interspaced short palindromic repeats (CRISPR) technology.
Adjuvant role of a T-type calcium channel blocker, TTA-A2, in lung cancer treatment with paclitaxel
Cancer Drug Resist 2021 Nov 14;4(4):996-1007.PMID:35582374DOI:10.20517/cdr.2021.54.
Aim: Chemoresistance is a prevalent issue in cancer treatment. Paclitaxel (PTX) is a microtubule-binding anticancer drug used in various cancer treatments. However, cancer cells often show chemoresistance against PTX with the help of P-glycoprotein (Pgp) - a drug efflux pump. It has also been observed that overexpressed T-type calcium channels (TTCCs) maintain calcium homeostasis in cancer cells, and calcium has a role in chemoresistance. Therefore, the aim of this study was to test the adjuvant role of TTA-A2, a TTCC blocker, in enhancing the anticancer effect of PTX on the A549 lung adenocarcinoma cell line. Methods: Morphology assay, calcium imaging assay, clonogenic assay, apoptosis assay, and real-time polymerase chain reaction (real-time PCR) were performed to find the adjuvant role of TTA-A2. Samples were treated with PTX at 10 nM concentration and TTA-A2 at 50 and 100 nM concentrations. PTX and TTA-A2 were used in the combination treatment at 10 and 100 nM concentrations, respectively. Results: Immunocytochemistry confirmed the expression of TTCC in A549 cells. Morphology assay showed altered morphology of A549 cells. The adjuvant role of TTA-A2 was observed in the calcium imaging assay in spheroids, in the clonogenic assay in monolayers, and in the apoptosis assay in both cultures. With real-time PCR, it was observed that, even though cells express the mRNA of Pgp, it is non-significant upon treatment with PTX and TTA-A2. Conclusion: TTA-A2 can be used as an adjuvant to reduce chemoresistance in cancer cells as well as to enhance the anticancer effect of the standard anticancer drug PTX. Being a potent TTCC inhibitor, TTA-A2 may also enhance the anticancer effects of other anticancer drugs.
T-type calcium channel antagonist, TTA-A2 exhibits anti-cancer properties in 3D spheroids of A549, a lung adenocarcinoma cell line
Life Sci 2020 Nov 1;260:118291.PMID:32810510DOI:10.1016/j.lfs.2020.118291.
Aims: Despite the advanced cancer treatments, there is increased resistance to chemotherapy and subsequent mortality. In lack of reliable data in monolayer cultures and animal models, researchers are shifting to 3D cancer spheroids, which represents the in vivo robust tumour morphology. Calcium is essential in cell signalling and proliferation. It is found that T-type calcium channels (TTCCs) are overexpressed in various cancer cells, supporting their increased proliferation. Many of the TTCCs blockers available could target other channels besides TTCCs, which can cause adverse effects. Therefore, we hypothesise that TTA-A2, a highly selective blocker towards TTCCs, can inhibit the growth of cancer spheroids, and provide an anti-cancer and an adjuvant role in cancer therapy. Methods: We studied TTA-A2 and paclitaxel (PTX-control drug) in lung adenocarcinoma cell line- A549, cancer cells and human embryonic kidney cell line- HEK 293, control cell, in their monolayer and spheroids forms for viability, proliferation, morphology change, migration, and invasion-after 48-96 h of treatment. Key findings: Though the results varied between the monolayer and spheroids studies, we found both anti-cancer as well as adjuvant effect of TTA-A2 in both the studies. TTA-A2 was able to inhibit the growth, viability, and metastasis of the cancer cells and spheroids. Differences in the results of two modes might explain that why drugs tested successfully in monolayer culture fail in clinical trials. Significance: This study establishes the role of TTA-A2, a potent TTCC blocker as an anti-cancer and adjuvant drug in reducing the viability and metastasis of the cancer cells.
Cross-modulation and molecular interaction at the Cav3.3 protein between the endogenous lipids and the T-type calcium channel antagonist TTA-A2
Mol Pharmacol 2014 Feb;85(2):218-25.PMID:24214826DOI:10.1124/mol.113.089581.
T-type calcium channels (T/Ca(v)3-channels) are implicated in various physiologic and pathophysiologic processes such as epilepsy, sleep disorders, hypertension, and cancer. T-channels are the target of endogenous signaling lipids including the endocannabinoid anandamide, the ω3-fatty acids, and the lipoamino-acids. However, the precise molecular mechanism by which these molecules inhibit T-current is unknown. In this study, we provided a detailed electrophysiologic and pharmacologic analysis indicating that the effects of the major N-acyl derivatives on the Ca(v)3.3 current share many similarities with those of TTA-A2 [(R)-2-(4-cyclopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide], a synthetic T-channel inhibitor. Using radioactive binding assays with the TTA-A2 derivative [(3)H]TTA-A1 [(R)-2-(4-(tert-butyl)phenyl)-N-(1-(5-methoxypyridin-2-yl)ethyl)acetamide], we demonstrated that polyunsaturated lipids, which inhibit the Ca(v)3.3 current, as NAGly (N-arachidonoyl glycine), NASer (N-arachidonoyl-l-serine), anandamide, NADA (N-arachidonoyl dopamine), NATau (N-arachidonoyl taurine), and NA-5HT (N-arachidonoyl serotonin), all displaced [(3)H]TTA-A1 binding to membranes prepared from cells expressing Ca(v)3.3, with Ki in a micromolar or submicromolar range. In contrast, lipids with a saturated alkyl chain, as N-arachidoyl glycine and N-arachidoyl ethanolamine, which did not inhibit the Ca(v)3.3 current, had no effect on [(3)H]TTA-A1 binding. Accordingly, bio-active lipids occluded TTA-A2 effect on Ca(v)3.3 current. In addition, TTA-Q4 [(S)-4-(6-chloro-4-cyclopropyl-3-(2,2-difluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)benzonitrile], a positive allosteric modulator of [(3)H]TTA-A1 binding and TTA-A2 functional inhibition, acted in a synergistic manner to increase lipid-induced inhibition of the Ca(v)3.3 current. Overall, our results demonstrate a common molecular mechanism for the synthetic T-channel inhibitors and the endogenous lipids, and indicate that TTA-A2 and TTA-Q4 could be important pharmacologic tools to dissect the involvement of T-current in the physiologic effects of endogenous lipids.