T-type calcium channels (Caₐ₃.2): recombinant human Caₐ₃.2 (IC₅₀ = 2 μM, voltage-dependent block), rat dorsal root ganglion (DRG) neuron low voltage-activated (LVA) currents (IC₅₀ = 8 μM) [1]
Other calcium channels (Caₐ₁.2, Caₐ₂.2): IC₅₀ > 30 μM (significantly less active) [1]

体外活性：ABT-639 是一种新型强效、外周作用、选择性 T 型 Ca2+ 通道阻滞剂，以电压依赖性方式阻断重组人 T 型 (Cav3.2) Ca2+ 通道 (IC50=2 μM) 并减弱大鼠 DRG 神经元中的低电压激活 (LVA) 电流 (IC50=8 μM)。 ABT-639 在其他 Ca2+ 通道（例如 Cav1.2 和 Cav2.2）上的活性明显较低（IC50>30 mM）。口服给药后，ABT-639 在大鼠膝关节疼痛模型中产生剂量依赖性镇痛作用（ED₅₀ = 2 mg/kg，口服）。 ABT-639（10-100 mg/kg，口服）还增加了多种神经性疼痛模型（例如脊神经结扎、CCI 和长春新碱诱导）的触觉异常性疼痛阈值。 [更正]。 ABT-639 不会减弱弗氏完全佐剂或角叉菜胶诱导的炎性疼痛模型中的痛觉过敏。在较高剂量（例如100-300 mg/kg）下，ABT-639 并未显着改变血流动力学或精神运动功能。 ABT-639 的镇痛作用为外周 T 型 (Ca(v)3.2) 通道在慢性疼痛状态中的作用提供了新的见解。激酶测定：细胞测定：ABT-639 以电压依赖性方式阻断重组人 T 型 (Cav3.2) Ca2+ 通道 (IC50=2 μM) 并减弱大鼠 DRG 神经元中的低电压激活 (LVA) 电流 (IC50) =8μM）。 ABT-639 在其他 Ca2+ 通道（例如 Cav1.2 和 Cav2.2）上的活性明显较低（IC50>30 mM）。 ABT-639 在啮齿类动物中具有高口服生物利用度 (%F=73)、低蛋白结合 (88.9%) 和低脑:血浆比 (0.05:1)。口服给药后

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1. 通道阻断活性：ABT-639 以电压依赖性方式阻断重组人源T型（Caₐ₃.2）钙通道，IC₅₀值为2 μM；可抑制大鼠背根神经节（DRG）神经元的低电压激活（LVA）钙电流，IC₅₀值为8 μM；该化合物对其他钙通道亚型（Caₐ₁.2、Caₐ₂.2）的活性显著降低，IC₅₀值均大于30 μM，体现出对T型（Caₐ₃.2）通道的高选择性[1]

ABT-639 减弱大鼠 DRG 神经元中的低电压激活 (LVA) 电流 (IC50=8 μM)，并以电压依赖性方式阻断重组人 T 型 (Cav3.2) Ca2+ 通道 (IC50=2 μM)。 ABT -639 在其他 Ca2+ 通道 (IC50>30 mM)（例如 Cav1.2 和 Cav2.2）上表现出显着较低的活性。在啮齿动物中，ABT-639 表现出低蛋白结合率 (88.9%)、低脑：血浆比率 (0.05:1) 和高口服生物利用度 (%F=73)。在膝关节疼痛大鼠模型中，口服 ABT-639 会产生剂量依赖性镇痛作用（ED50=2 mg/kg，口服）。在各种神经性疼痛模型中，例如脊神经结扎、CCI、长春新碱诱导的和辣椒素继发性超敏反应，ABT-639（10-100 mg/kg，口服）也会提高触觉异常性疼痛阈值。在角叉菜胶或弗氏完全佐剂诱导的炎性疼痛模型中，ABT-639 不会减轻痛觉过敏。较高剂量的 ABT-639（例如 100-300 mg/kg）对血流动力学或精神运动功能没有明显影响。 ABT-639 的镇痛特性为慢性疼痛状态下外周 T 型 (Cav3.2) 通道的功能提供了新的见解[1]。

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1. 伤害性疼痛模型中的镇痛作用：大鼠膝关节疼痛模型中，口服给予ABT-639 可产生剂量依赖性镇痛效果，ED₅₀值为2 mg/kg（口服）[1]
2. 神经性疼痛模型中的作用：ABT-639（10-100 mg/kg，口服）可提高多种大鼠神经性疼痛模型（脊神经结扎、慢性压迫性损伤（CCI）、长春新碱诱导的神经性疼痛）的触觉异常性疼痛阈值[1]
3. 炎症性疼痛模型中的作用：ABT-639 无法缓解完全弗氏佐剂或角叉菜胶诱导的大鼠炎症性疼痛模型中的痛觉过敏[1]
4. 血流动力学和精神运动影响：高剂量（100-300 mg/kg，口服）ABT-639 未显著改变大鼠的血流动力学（如血压、心率）或精神运动功能[1]

1. 重组人源Caₐ₃.2通道活性实验：将重组人源Caₐ₃.2 T型钙通道制备物暴露于不同浓度的ABT-639，并设置不同电压条件；检测通道阻断活性，确定IC₅₀值（2 μM），验证ABT-639 的电压依赖性阻断特征[1]
2. 大鼠DRG神经元LVA电流实验：分离并培养原代大鼠DRG神经元，用不同浓度的ABT-639 处理；采用膜片钳技术记录LVA钙电流，定量ABT-639 对该电流的抑制作用，计算IC₅₀值（8 μM）[1]
3. 其他钙通道活性实验：将Caₐ₁.2、Caₐ₂.2钙通道制备物用ABT-639（浓度高于30 μM）处理；检测通道活性，确定IC₅₀值（>30 μM），证实ABT-639 对这些亚型的低活性[1]

1. 大鼠DRG神经元培养及LVA电流检测：分离、纯化大鼠DRG神经元并在适宜培养基中培养；待神经元达到所需状态后，与不同浓度的ABT-639 共孵育；采用膜片钳电生理技术检测低电压激活钙电流，评估ABT-639 对该电流的抑制作用，确定其对大鼠DRG神经元LVA电流的IC₅₀值[1]

10-100 mg/kg, p.o.
Rat model of knee joint pain

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1. Rat knee joint pain model (nociceptive pain): Male Sprague-Dawley rats were used to establish the knee joint pain model; ABT-639 was administered orally at different doses, and the antinociceptive effect was evaluated to determine the ED₅₀ value (2 mg/kg, p.o.) [1]
2. Neuropathic pain models (spinal nerve ligation, CCI, vincristine-induced): Male Sprague-Dawley rats were used to establish respective neuropathic pain models; ABT-639 was administered orally at doses of 10-100 mg/kg, and tactile allodynia thresholds were measured at specified time points to assess the therapeutic effect [1]
3. Inflammatory pain models (complete Freund's adjuvant/carrageenan-induced): Male Sprague-Dawley rats were injected with complete Freund's adjuvant or carrageenan to induce inflammatory pain; ABT-639 was administered orally, and hyperalgesia was evaluated to confirm the lack of effect of ABT-639 on inflammatory pain [1]
4. Hemodynamic/psychomotor function assessment: Male Sprague-Dawley rats were administered ABT-639 at high doses (100-300 mg/kg, p.o.); hemodynamic parameters (e.g., blood pressure, heart rate) and psychomotor function were monitored over a specified period to evaluate potential adverse effects [1]
5. Pharmacokinetic assessment in rodents: Rodents (specific strain not specified) were administered ABT-639 orally; plasma and brain samples were collected at different time points, and drug concentrations were measured to determine oral bioavailability, plasma protein binding, and brain:plasma ratio [1]

1. Oral bioavailability: ABT-639 has high oral bioavailability in rodents, with a %F value of 73% [1]
2. Plasma protein binding: The plasma protein binding rate of ABT-639 in rodents is 88.9% (low protein binding) [1]
3. Tissue distribution: ABT-639 shows a low brain:plasma ratio (0.05:1) in rodents, indicating limited penetration across the blood-brain barrier and peripheral selectivity [1]

1. Hemodynamic/psychomotor toxicity: At doses up to 300 mg/kg (oral administration), ABT-639 did not cause significant alterations in hemodynamic parameters (e.g., blood pressure, heart rate) or psychomotor function in rats, indicating a lack of acute toxicity related to these endpoints [1]
2. Plasma protein binding: The plasma protein binding rate of ABT-639 is 88.9% (rodents), with no reported drug-drug interactions related to protein binding displacement [1]

[1]. A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats. Biochem Pharmacol. 2014 Jun 15;89(4):536-44.

ABT-639 is under investigation in clinical trial NCT01345045 (A Multicenter Study Comparing the Analgesic Effects and Safety of ABT-639 Compared to Placebo in Subjects With Diabetic Neuropathic Pain).
T-type Calcium Channel Blocker ABT-639 is an orally bioavailable, CaV3.2 T-type calcium channel blocker with potential anti-hyperalgesic activity. Upon oral administration, ABT-639 selectively binds to and blocks the CaV3.2 isoform of the low voltage-gated T-type calcium channels located in peripheral sensory neurons. This prevents the influx of calcium ions into the cell upon membrane depolarization. The inhibition of both neuronal hyperexcitability and firing of nociceptive, peripheral sensory neurons induces an anti-nociceptive effect. The expression of the CaV3.2 T-type channels plays a key role in nociceptive and neuropathic pain.

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1. Mechanism of action: ABT-639 is a peripherally acting, selective T-type (Caₐ₃.2) calcium channel blocker; activation of T-type Ca²⁺ channels contributes to nociceptive signaling by facilitating action potential bursting and modulation of membrane potentials during neuronal hyperexcitability, and ABT-639 attenuates this signaling by blocking Caₐ₃.2 channels [1]
2. Therapeutic profile: ABT-639 is effective in reducing nociceptive pain (knee joint pain) and neuropathic pain in rats but has no effect on inflammatory pain, highlighting its selective efficacy for specific pain states; its peripheral selectivity (low brain penetration) and lack of hemodynamic/psychomotor toxicity at high doses support its potential as a safe therapeutic agent for chronic pain [1]
3. Background: The role of T-type Ca²⁺ channels (Caₐ₃.2) in chronic pain is supported by gene knockdown studies, which showed reduced LVA currents in DRG neurons and attenuated neuropathic pain in the CCI model; ABT-639 was developed as a novel peripherally acting blocker targeting this channel subtype [1]

C20H20CLF2N3O3S

455.91

455.088

1235560-28-7

ABT-639 hydrochloride;1235560-31-2

46851313

White to off-white solid powder

1.5±0.1 g/cm3

612.2±65.0 °C at 760 mmHg

324.0±34.3 °C

0.0±1.8 mmHg at 25°C

1.653

2.6

78.1

1

7

4

30

737

1

C1C[C@@H]2CN(CCN2C1)C(=O)C3=CC(=C(C=C3Cl)F)S(=O)(=O)NC4=CC=CC=C4F

AGPIHNZOZNKRGT-CYBMUJFWSA-N

InChI=1S/C20H20ClF2N3O3S/c21-15-11-17(23)19(30(28,29)24-18-6-2-1-5-16(18)22)10-14(15)20(27)26-9-8-25-7-3-4-13(25)12-26/h1-2,5-6,10-11,13,24H,3-4,7-9,12H2/t13-/m1/s1

5-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl]-4-chloro-2-fluoro-N-(2-fluorophenyl)benzenesulfonamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)