α1-adrenoceptor

体外活性：Terazosin 在 PC-3 和人良性前列腺细胞中诱导细胞毒性，IC50 超过 100 μM。特拉唑嗪还有效抑制培养的人脐静脉内皮细胞中血管内皮生长因子诱导的增殖和管形成（IC50 分别为 9.9 和 6.8 μM）。 细胞测定：为了确定细胞毒性作用的作用方式，本研究中使用了几种鉴定技术。使用末端脱氧核苷酸转移酶脱氧尿苷三磷酸缺口末端标记原位检测凋亡细胞。结果显示，用特拉唑嗪 (100 μM) 处理 PC-3 细胞 12 小时后出现阳性反应。

特拉唑嗪对运动活动和僵直症产生剂量依赖性的完全抑制作用。脑室内注射该拮抗剂可保护纹状体和大脑皮质 α1 受体，但不能保护纹状体或皮质 D1 受体免受 N-乙氧基羰基-2-乙氧基-1,2-二羟基喹啉体内烷基化。心室内注射特拉唑嗪还会导致体温过低和呼吸频率降低，表明交感神经流出减少。特拉唑嗪不会损害水平钢丝测试的表现或游泳测试中协调运动的能力。 Terazosin 在裸鼠中显着抑制血管内皮生长因子诱导的血管生成，IC50 为 7.9 μM，表明其具有比细胞毒作用更有效的抗血管生成作用。

本研究中使用了PC-3细胞和人良性前列腺细胞的原代培养物。使用3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四氮唑测定法和乳酸脱氢酶释放反应检测细胞毒性作用。在裸鼠模型中测定体内血管生成作用，然后进行组织学检查和血红蛋白检测定量。在培养的人脐静脉内皮细胞中进行了细胞迁移、增殖和管形成的体外测定。结果terazosin/特拉唑嗪可诱导PC-3和人类良性前列腺细胞产生细胞毒性，IC50超过100微M。末端脱氧核苷酸转移酶脱氧尿苷三磷酸缺口末端标记和乳酸脱氢酶释放反应阳性与特拉唑嗪诱导的细胞毒性有关，表明细胞凋亡和坏死死亡。此外，特拉唑嗪作用引起的细胞毒性不是喹唑啉基结构的常见特征。特拉唑嗪显著抑制血管内皮生长因子诱导的裸鼠血管生成，IC50为7.9微M。，表明其抗血管生成作用比细胞毒性作用更强。特拉唑嗪还有效地抑制了血管内皮生长因子诱导的培养的人脐静脉内皮细胞的增殖和管形成（IC50分别为9.9和6.8微摩尔）。 结论：我们的数据表明，terazosin/特拉唑嗪通过抑制内皮细胞的增殖和管形成显示出直接的抗血管生成活性。这一作用可能部分解释了特拉唑嗪的体内抗肿瘤潜力[3]。

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在当前的研究中，采用了各种鉴定技术来确定细胞毒性作用的作用方式。通过末端脱氧核苷酸转移酶脱氧尿苷三磷酸缺口末端标记，可以原位鉴定凋亡细胞。 PC-3细胞用100μM特拉唑嗪处理12小时后，结果显示阳性反应。

terazosin, a water-soluble alpha 1 antagonist that can be administered in high doses intraventricularly was used to study the relationship between brain alpha 1 adrenoceptor neurotransmission and behavioral activation in the mouse. The antagonist was found to produce a dose-dependent, complete inhibition of motor activity and catalepsy which were reversed preferentially by coinfusion of an alpha 1 agonist (phenylephrine) compared to a D1 (SKF38393) or a D2 agonist, (quinpirole). Blockade of central beta-1 (betaxolol), alpha-2 (RX821002) or beta-2 (ICI 118551) adrenoceptors had smaller or non-significant effects. Terazosin's selectivity for alpha 1 receptors versus dopaminergic receptors was verified under the present conditions by showing that the intraventricularly administered antagonist protected striatal and cerebral cortical alpha 1 receptors but not striatal or cortical D1 receptors from in vivo alkylation by N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroxyquinoline. That its effect was due to blockade of brain rather than peripheral receptors was shown by the finding that intraperitoneal doses of terazosin three to 66 times greater than the maximal intraventricular dose produced less behavioral inhibition. Intraventricular terazosin also produced hypothermia and a reduced respiratory rate suggestive of a reduced sympathetic outflow. However, external heat did not affect the inactivity, and captopril, a hypotensive agent, did not mimic it. Terazosin did not impair performance on a horizontal wire test or the ability to make co-ordinated movements in a swim test suggesting that its activity-reducing effect was not due to sedation and may have a motivational or sensory gating component. It is concluded that central alpha 1-noradrenergic neurotransmission is required for behavioral activation to environmental change in the mouse and may operate on sensorimotor and motivational processes.[2]

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Dissolved in water; 0.05 mg/kg; oral gavage

Mice

Absorption, Distribution and Excretion
Approximately 90%.
Approximately 10% of the oral dose is excreted unchanged in the urine and approximately 20% is excreted in the feces. 40% of the total dose is eliminated in urine and 60% of the total dose is eliminated in the feces.
25L to 30L.
Plasma clearance is 80mL/min and renal clearance is 10mL/min.

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Metabolism / Metabolites
The majority of terazosin is hepatically metabolized. The metabolites recovered include 6-O-demethyl terazosin, 7-O-methyl terazosin, a piperozine derivative, and a diamine derivative.
Hepatic. One of the four metabolites identified (piperazine derivative of terazosin) has antihypertensive activity.
Route of Elimination: Approximately 10% of an orally administered dose is excreted as parent drug in the urine and approximately 20% is excreted in the feces.
Half Life: 12 hours

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Biological Half-Life
Terazosin has a mean half life 12 hours though this can be as high as 14 hours in patients over 70 years and as low as 11.4 hours in patients 20 to 39 years old.

Toxicity Summary
Terazosin selectively and competitively inhibits vascular postsynaptic alpha(1)-adrenergic receptors, resulting in peripheral vasodilation and a reduction of vascular resistance and blood pressure. Unlike the nonselective alph-adrenergic blockers phenoxybenzamine and phentolamine, terazosin does not block presynaptic alpha(2)-receptors and, hence, does not cause reflex activation of norepinephrine release to produce reflex tachycardia.

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Hepatotoxicity
Terazosin has been associated with a low rate of serum aminotransferase elevations that in controlled trials was no higher than with placebo therapy. These elevations were transient and did not require dose modification. Instances of serum enzyme elevations, but no instances of clinically apparent acute liver injury with jaundice due to terazosin, have been published. Furthermore, product labels do not include discussion of hepatic toxicity. Cholestatic hepatitis and jaundice have been reported with other alpha-adrenergic blockers. Thus, acute symptomatic liver injury due to terazosin must be exceedingly rare if it occurs at all.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the use of terazosin during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information in nursing mothers was not found as of the revision date. However, the pharmacologically similar drug prazosin does not affect serum prolactin concentration in patients with hypertension. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Protein Binding
90-94%.

[1]. Journal of Neurochemistry. 2002, 83:623-634.

[2]. Neuroscience . 1999;94(4):1245-52.

[3]. J Urol . 2003 Feb;169(2):724-9.

Terazosin Hydrochloride is the hydrochloride salt form of terazosin, a quinazoline derivative with adrenergic antagonistic property. Terazosin hydrochloride selectively inhibits alpha-1 adrenergic receptors, resulting in vasodilation leading to decreased peripheral vascular resistance and a reduced venous return to the heart as well as decreased urethral resistance, which potentially improving urine flow and symptoms related to benign prostatic hyperplasia. In addition, terazosin decreases low-density lipoproteins (LDL) and triglycerides while increasing the concentration of high-density lipoproteins (HDL).
See also: Terazosin (has active moiety).

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We had previously reported that systemic overexpression of the α1B-adrenergic receptor (AR) in a transgenic mouse induced a neurodegenerative disease that resembled the parkinsonian-like syndrome called multiple system atrophy (MSA). We now report that our mouse model has cytoplasmic inclusion bodies that colocalize with oligodendrocytes and neurons, are positive for α-synuclein and ubiquitin, and therefore may be classified as a synucleinopathy. α-Synuclein monomers as well as multimers were present in brain extracts from both normal and transgenic mice. However, similar to human MSA and other synucleinopathies, transgenic mice showed an increase in abnormal aggregated forms of α-synuclein, which also increased its nitrated content with age. However, the same extracts displayed decreased phosphorylation of α-synuclein. Other traits particular to MSA such as Purkinje cell loss in the cerebellum and degeneration of the intermediolateral cell columns of the spinal cord also exist in our mouse model but differences still exist between them. Interestingly, long-term therapy with the α1-AR antagonist, terazosin, resulted in protection against the symptomatic as well as the neurodegeneration and α-synuclein inclusion body formation, suggesting that signaling of the α1B-AR is the cause of the pathology. We conclude that overexpression of the α1B-AR can cause a synucleinopathy similar to other parkinsonian syndromes.[1]

C19H26CLN5O4

423.9

423.17

C, 53.84; H, 6.18; Cl, 8.36; N, 16.52; O, 15.10

63074-08-8

Terazosin hydrochloride dihydrate; 70024-40-7; (R)-Terazosin; 109351-34-0; (S)-Terazosin; 109351-33-9; Terazosin; 63590-64-7

44383

White to off-white solid powder

1.3±0.1 g/cm3

664.5±65.0 °C at 760 mmHg

355.7±34.3 °C

0.0±2.0 mmHg at 25°C

1.636

-0.96

103.04

2

8

4

29

544

0

O=C(N1CCN(C2=NC(N)=C3C=C(OC)C(OC)=CC3=N2)CC1)C4OCCC4.[H]Cl

IWSWDOUXSCRCKW-UHFFFAOYSA-N

InChI=1S/C19H25N5O4.ClH/c1-26-15-10-12-13(11-16(15)27-2)21-19(22-17(12)20)24-7-5-23(6-8-24)18(25)14-4-3-9-28-14;/h10-11,14H,3-9H2,1-2H3,(H2,20,21,22);1H

[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(oxolan-2-yl)methanone;hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
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