α-adrenergic receptor

体外活性：甲磺酸酚妥拉明在海绵体膜中以相对较高的亲和力取代选择性 α 1 受体拮抗剂 [125I]HEAT 和 [3H]prazosin 以及 α2 受体拮抗剂 [3H]rauwolscine 和 [3H]RX 821002 的结合。甲磺酸酚妥拉明会导致预先用肾上腺素激动剂去氧肾上腺素、去甲肾上腺素、羟甲唑啉和 UK 14,304 以及非肾上腺素收缩剂内皮素和 KCl 收缩的勃起组织条产生浓度依赖性松弛。 Phentolamine mesylate 通过直接拮抗 α1 和 2 肾上腺素能受体，以及通过非肾上腺素能、内皮介导的机制（提示一氧化氮合酶激活）间接功能拮抗，诱导海绵体勃起组织松弛。酚妥拉明是一种α-肾上腺素能拮抗剂，可阻断与牙科麻醉制剂中使用的肾上腺素相关的血管收缩，从而增强局部麻醉剂从注射部位的全身吸收。

在小鼠中，酚妥拉明（5–20 mg/kg；腹腔注射）可减轻 DOPS（4 mg/kg，腹腔注射）引起的癫痫发作，并成功预防士的宁（2 mg/kg，腹腔注射）引起的癫痫发作[2]。腹腔注射酚妥拉明 (1 mg/kg) 通过阻断小鼠 B 细胞中的 a2A 肾上腺素受体来增强胰岛素的产生 [3]。

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1.研究了一些去甲肾上腺素能药物对马钱子碱诱导的小鼠癫痫发作的影响。2.士的宁（0.5-4mg/kg，i.p.）剂量依赖性地产生强直性癫痫发作。3.DOPS（4-8mg/kg，i.p.）显著缩短了士的宁（2mg/kg，i.p。同样，DOPS（4 mg/kg，i.p.）有效地增加了士的宁（1 mg/kg，i.p..）诱导的癫痫发作的发生率，并显著缩短了癫痫发作的潜伏期。4.丙咪嗪（20-40mg/kg，腹腔注射）和帕吉林（200mg/kg，腹腔注射”）显著缩短了士的宁（2mg/kg，腹腔注射“）诱导的癫痫发作的潜伏期。5.酚妥拉明（5-20mg/kg，i.p.）有效拮抗士的宁（2mg/kg，i.p.m.）引起的癫痫发作。此外，酚妥拉明（10mg/kg，i.p.）减弱了DOPS（4mg/kg，i.p。6.普萘洛尔（0.5-2mg/kg，i.p.）和哌唑嗪（1-2mg/kg，i.p..）降低了士的宁（2mg/kg，i.p.m.）引起的癫痫发作的发生率，并显著延迟了癫痫发作的潜伏期。7.利血平（5-10mg/kg，i.p.）显著延长了士的宁（2mg/kg，i.p..）诱导的癫痫发作的潜伏期。8.可乐定（0.25-1mg/kg，腹腔注射）剂量依赖性地显著拮抗士的宁（2mg/kg，腹腔注射。）诱导的癫痫发作。9.依他唑嗪（1-4mg/kg，i.p.）以剂量相关的方式显著缩短了士的宁（2mg/kg，i.p.m.）诱导的癫痫发作的潜伏期。同样，伊达唑嗪（2 mg/kg，腹腔注射）显著增强了士的宁（1 mg/kg，腹腔内注射）引起的癫痫发作。Idazoxan（4 mg/kg，i.p.）显著拮抗可乐定（1 mg/kg，i.p..）对士的宁（2 mg/kg，i.i.p.）诱导的癫痫发作的保护作用。10.二硫仑（3 x 25-3 x 100 mg/kg，腹腔注射）显著减轻了士的宁（2 mg/kg，腹腔内注射）诱导的癫痫发作。DOPS（4 mg/kg，i.p.）显著增强了双硫仑（3 x 100 mg/kg，i.p..）预处理动物的士的宁癫痫发作。11.这些结果表明，去甲肾上腺素能神经传递的增强会增强小鼠士的宁的发作[2]。

在无细胞系统中，通过将特异性和选择性放射性标记的配体置换到α1和2肾上腺素能受体上来研究酚妥拉明的结合活性。在器官浴室中研究了酚妥拉明介导的人和兔海绵体肾上腺素能和非肾上腺素能预收缩勃起组织条的松弛的生理活性。Int J Impot Res . 1998 Dec;10(4):215-23.

在体外研究了NO-cGMP依赖途径对甲磺酸酚妥拉明诱发的兔海绵体非肾上腺素能、非胆碱能舒张的贡献。刺激兔海绵体的非肾上腺素能、非胆碱能神经元可引发频率相关的弛豫，L-NAME（NO合酶抑制剂）或ODQ（鸟苷酸环化酶抑制剂）可显著减弱这种弛豫。此外，钠通道阻断剂河豚毒素消除了电场刺激诱导的兔海绵体松弛，表明神经元释放NO介导了电场刺激的松弛。甲磺酸酚妥拉明（30和100 nM）剂量依赖性地增强电场刺激诱导的兔海绵体松弛。哌唑嗪（30μM）和育亨宾（30μm）未能影响甲磺酸酚妥拉明介导的非肾上腺素能、非胆碱能兔阴茎平滑肌放松，表明酚妥拉明放松兔海绵体，与α肾上腺素能受体阻断无关。相比之下，用L-NAME预处理兔海绵体条可显著减弱电场刺激，对甲磺酸酚妥拉明产生舒张作用，表明甲磺酸酚托拉明通过激活NO合酶来放松兔海绵体。数据表明，甲磺酸酚妥拉明通过激活NO合酶来放松兔海绵体的非肾上腺素能非胆碱能神经元，并且与α肾上腺素能受体阻断无关. Fundam Clin Pharmacol . 2001 Feb;15(1):1-7.

Animal/Disease Models: WT mice [3]
Doses: 1 mg/kg
Route of Administration: IP
Experimental Results: Blood glucose diminished and insulin levels increased.

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Effects of (+/-)-efaroxan, 5 mg kg(-1), and phentolamine, 1 mg kg(-1), on blood glucose and insulin levels were compared with those of the non-imidazoline alpha2-adrenoceptor antagonist [8aR,12aS,13aS]-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]naphthyridine (RS79948-197), 1 mg kg(-1), and the sulphonylurea glibenclamide, in alpha2A-KO and control (wild type (WT)) mice. Key results: In fed WT mice, (+/-)-efaroxan, phentolamine and RS79948-197 reduced blood glucose and increased insulin levels. Fasting abolished these effects. In fed alpha2A-KO mice, (+/-)-efaroxan, phentolamine and RS79948-197 did not alter blood glucose or insulin levels, and in fasted alpha2A-KO mice, blood glucose levels were increased. Glibenclamide, at a dose only moderately efficacious in WT mice (5 mg kg(-1)), caused severe hyperinsulinaemia and hypoglycaemia in alpha2A-KO mice. This was mimicked in WT mice by co-administration of RS79948-197 with glibenclamide. Conclusions and implications: These results suggest that (+/-)-efaroxan and phentolamine increase insulin secretion by inhibition of beta-cell alpha2A-adrenoceptors, and demonstrate a critical role for alpha2A-adrenoceptors in limiting sulphonylurea-induced hyperinsulinaemia and hypoglycaemia.[3]

Absorption, Distribution and Excretion
Phentolamine reaches peak plasma concentration within 10 to 20 minutes after submucosal administration. Peak plasma concentrations (Cmax) are higher in larger children. After topical instillation of 0.75% phentolamine eye drops, peak plasma concentrations are reached within 15 minutes to 1 hour, with a median of 0.45 ng/mL. Approximately 13% of a single intravenous dose is excreted unchanged in the urine. Although information on the distribution of phentolamine is limited, it has been reported to cross the blood-brain barrier. The time to peak concentration (Tmax) is 30 to 60 minutes. Protein binding is less than 72%. It is primarily metabolized in the liver, with 80% excreted by the kidneys (of which 10% to 13% is excreted unchanged) and 20% by feces. The activity of orally administered phentolamine is only about 20% of that of parenteral administration. Approximately 10% of the parenteral dose is recovered in the urine as the active drug; the fate of the remainder is unknown. It is currently unknown whether this drug crosses the placenta or appears in breast milk. Metabolites/Metabolites: Known metabolites of phentolamine include [3-[N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-4-methylaniline]phenyl]hydrosulfate. Biological Half-Life: The half-life of intravenously administered phentolamine is 19 minutes. The terminal elimination half-life of submucosal administration of phentolamine is approximately 2 to 3 hours. The elimination half-life of intravenously administered phentolamine is 19 minutes, and the elimination half-life of oral administration is 5 to 7 hours.

Subcutaneous injection of LDLo 275 mg/kg in rats, Japanese Pharmacopoeia, 6(667), 1982
Intravenous injection of LDLo 75 mg/kg in rats, Japanese Pharmacopoeia, 6(667), 1982
Intravenous injection of LD50 75 mg/kg in mice, Pharmacology Journal, 5(101), 1974
Subcutaneous injection of LDLo 200 mg/kg in rabbits, Japanese Pharmacopoeia, 6(667), 1982
Intravenous injection of LDLo 35 mg/kg in rabbits, Japanese Pharmacopoeia, 6(667), 1982
Interactions
Pimozide is a potent antagonist of (+) amphetamine, diethylacetone, malindole, and phentermine in anorexia in mice. Phentolamine and propranolol did not produce such antagonistic effects, but either enhanced or had no effect on drug-induced anorexia.

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Non-human toxicity values
Oral LD50 in rats: 1250 mg/kg
Oral LD50 in mice: 1000 mg/kg

[1]. Goldstein I I. Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction. Int J Impot Res. 2000 Mar;12(S1):S75-S80.

[2]. Strychnine-induced seizures in mice: the role of noradrenaline. Prog Neuropsychopharmacol Biol Psychiatry. 1994 Jul;18(4):753-63.

[3]. alpha2A-adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice. Br J Pharmacol. 2008 Jul;154(6):1287-96.

Therapeutic Uses
Adrenergic alpha receptor blocker; antihypertensive drug; sympathetic nerve blocker. Phentolamine is primarily used for the diagnosis of pheochromocytoma and for controlling or preventing paroxysmal hypertension before or during pheochromocytoma resection. /See US product label for usage details/ OraVerse is indicated for reversing soft tissue anesthesia, i.e., lip and tongue anesthesia, and for corresponding functional impairments caused by submucosal injection of local anesthetics containing vasoconstrictors in the oral cavity. /See US product label for usage details/ While no single chemical or pharmacological assay is entirely reliable, measuring the concentration of catecholamines in the blood and/or the excretion of catecholamines or their metabolites in the urine is the safest and most reliable method for diagnosing pheochromocytoma. A phentolamine test may be used when further confirmation of pheochromocytoma is required and the potential benefit of the test outweighs the possible risks. The phentolamine test is more reliable in detecting pheochromocytoma in patients with persistent hypertension than in patients with paroxysmal hypertension, but has no diagnostic value in patients with normal blood pressure at the time of the test. A sudden and significant drop in blood pressure following parenteral administration of phentolamine in hypertensive patients may indicate the presence of pheochromocytoma. However, false negative and false positive results in the phentolamine test are common. /See US product label for usage details/
For more complete data on the therapeutic uses of phentolamine (10 types), please visit the HSDB record page.

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Drug Warnings
Pentolamine may cause acute or persistent hypotension, tachycardia, arrhythmias, and angina, especially after parenteral administration. Myocardial infarction and cerebral vasospasm or occlusion have been reported occasionally after parenteral administration of phentolamine, usually accompanied by significant hypotension and shock-like status. There have been cases of death following intravenous administration of phentolamine for the diagnosis of pheochromocytoma.
Patients receiving phentolamine treatment have reported symptoms such as fatigue, dizziness, flushing, orthostatic hypotension, and nasal congestion. Gastrointestinal adverse reactions are common, including abdominal pain, nausea, vomiting, diarrhea, and exacerbation of peptic ulcers; these adverse reactions usually limit the long-term use of phentolamine. When phentolamine and papaverine are used in combination (not approved in the US) to treat erectile dysfunction, priapism may occasionally occur. Priapism is a medical emergency that, if left untreated, can lead to penile tissue damage and permanent loss of sexual function. Therefore, if an erection lasts longer than 4 hours or is accompanied by severe pain, the patient should be advised to seek immediate medical attention; if medical attention is not available, other emergency medical assistance should be sought. Other complications of the combined use of phentolamine and papaverine include transient pain (including referred pain to the glans penis), burning sensation, and paresthesia. Many patients have experienced penile ecchymosis, and superficial penile hematoma and bruising have also been reported. Fibrotic changes (e.g., penile induration, lumps, but not necessarily located at the injection site) have been reported, including bilateral corpora cavernosa fibrosis. Reports of penile embolism are rare; one patient experienced priapism, deep vein thrombosis, and a fatal pulmonary embolism. Systemic adverse reactions to the drug have also been reported (e.g., facial flushing, dizziness, decreased blood pressure, metallic taste in the mouth). It is currently unknown whether phentolamine mesylate is excreted into breast milk. Because phentolamine mesylate can cause serious adverse reactions in breastfeeding infants, the importance of the drug to the mother should be weighed when deciding whether to discontinue breastfeeding or discontinue the drug. For more complete data on phentolamine (7 of 7), please visit the HSDB record page.

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Pharmacodynamics
Phentolamine produces a relatively short-duration alpha-adrenergic blockade. Phentolamine can cause vascular smooth muscle and pupillary dilation. When used in ophthalmic solutions, pupillary dilation typically begins within 30 minutes and reaches its maximum effect within 60 to 90 minutes. Pupil dilation lasts for at least 24 hours. Phentolamine also has direct but less pronounced positive inotropic and positive chronotropic effects on the myocardium, and vasodilatory effects on vascular smooth muscle; however, phentolamine is not considered to affect contractile function or adenylate cyclase function. High doses can lead to mild sympathetic nerve blockade. Some evidence suggests that phentolamine can also stimulate β-adrenergic receptors, thereby causing peripheral vasodilation. Phentolamine has been shown to stimulate insulin secretion, which may be related to its blocking effect on ATP-sensitive potassium channels.

C17H19N3O

281.359

281.152

C, 72.57; H, 6.81; N, 14.94; O, 5.69

50-60-2

Phentolamine hydrochloride;73-05-2;Phentolamine mesylate;65-28-1

5775

White to off-white solid powder

1.2±0.1 g/cm3

551.0±45.0 °C at 760 mmHg

177 - 178ºC

287.0±28.7 °C

0.0±1.5 mmHg at 25°C

1.626

3.6

47.86

2

3

4

21

363

0

MRBDMNSDAVCSSF-UHFFFAOYSA-N

InChI=1S/C17H19N3O/c1-13-5-7-14(8-6-13)20(12-17-18-9-10-19-17)15-3-2-4-16(21)11-15/h2-8,11,21H,9-10,12H2,1H3,(H,18,19)

3-[N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-4-methylanilino]phenol

C-7337; C-7337 Ciba; HSDB-3382; C7337; 50-60-2; Regitine; Fentolamin; Regitin; Dibasin; Fentolamina; Phentolaminum; C7337 Ciba; HSDB3382;; Phentolamine

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
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6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。