5-HT2/3 Receptors

在放射配体结合和全细胞电压钳实验中研究了米安色林和ORG3770对小鼠神经母细胞瘤N1E-115细胞中5-羟色胺5-HT3受体的立体选择性作用。米安色林和ORG3770及其对映异构体降低了[3H]GR65630与N1E-115细胞匀浆中5-HT3识别位点的特异性结合。米安色林和ORG3770的更强效（R）对映异构体的pKi值分别为8.44和8.62。米安色林和ORG3770的（R）对映异构体的效力是其各自（S）对映体的15倍和37倍。外消旋体的效力仅比相应的（R）对映异构体低1.9倍和3.3倍。在电压钳实验中，（R）对映异构体阻断了5-羟色胺（5-HT）诱导的离子电流，其中（R）米安色林的pIC50值为8.52，ORG3770的（R）对映异构体为8.26。米安色林和ORG3770的（R）对映异构体在阻断5-羟色胺诱导的离子电流方面比其各自的（S）对映体强24倍和145倍。外消旋体的效力比相应的（R）对映异构体低6倍和13倍。此外，ORG3770的（R）对映体对5-羟色胺诱导的离子电流的阻断被其低浓度的（S）对映异构体部分逆转。结果表明，这两种对映体以相互依赖的方式阻断5-HT3受体介导的离子电流[2]。

独特的去甲肾上腺素能和特异性5-羟色胺能抗抑郁药米氮平具有镇痛作用。它具有光学活性，目前以外消旋体的形式销售。在急性疼痛的动物模型中，已经表明对映体表现出不同的作用：R（-）-对映体显示出抗-、S（+）-对异构体的促痛感特性，而外消旋体在低剂量下具有镇痛作用，在高剂量应用后具有深度促痛感。本研究旨在评估米氮平在神经性疼痛中的潜在对映选择性作用。在神经性疼痛的慢性收缩损伤模型中，Wistar大鼠鞘内注射（+/-）-米氮平和对映异构体。所有物质的剂量均在0.001至1mg/kg之间，并采用随机和盲法与赋形剂进行比较。评估热痛觉过敏和机械性异常性疼痛。与急性疼痛结果相反，只有外消旋米氮平在48小时内表现出显著的持续镇痛作用。在所有剂量下都观察到了镇痛作用，最大剂量在0.01mg/kg范围内。令人惊讶的是，在任何剂量或时间，对映体都没有促镇痛作用。我们的研究结果表明，这两种对映体的协同作用对于治疗神经性疼痛具有显著的镇痛作用。我们的研究没有发现单独使用R（-）或S（+）-米氮平的证据。由于（+/-）-米氮平的独特特性及其在急性疼痛中的有效性，我们的研究结果表明，外消旋米氮平可能是一种特别有用的抗抑郁药，用于辅助治疗慢性神经性疼痛状态，并可能为当前的治疗选择提供额外的益处。[Brain Res Bull 2009 Apr 6;79(1):63-8]

The unique noradrenergic and specific serotonergic antidepressant mirtazapine acts antinociceptive. It is optically active and currently marketed as racemate. In an animal model of acute pain it has been shown that the enantiomers exhibit differential effects: the R(-)-enantiomer showed anti-, the S(+)-enantiomer pronociceptive properties while the racemate acted antinociceptive at low doses and profoundly pronociceptive after high-dose application. Aim of the present study was to evaluate potential enantioselective effects of mirtazapine in neuropathic pain. In a chronic constriction injury model of neuropathic pain, Wistar rats were injected (+/-)-mirtazapine and the enantiomers intrathecally. All substances were dosed between 0.001 and 1mg/kg and compared to vehicle in a randomized and blinded approach. Thermal hyperalgesia and mechanical allodynia were assessed. In contrast to the acute pain results, only racemic mirtazapine exerted significant sustained analgesic effects up to 48 h. Antinociception was observed at all dosages with a maximum in the range of 0.01 mg/kg. Surprisingly, neither enantiomer was pro- nor antinociceptive at any dose or time. Our findings suggest that the synergism of both enantiomers is required to evoke a significant analgesic effect for the treatment of neuropathic pain. Our study gained no evidence for the use of either R(-) nor S(+)-mirtazapine alone. Due to the unique characteristics of (+/-)-mirtazapine and its proven efficacy in acute pain our results suggest that racemic mirtazapine may be a particularly useful antidepressant in the adjunctive treatment of chronic neuropathic pain states and could provide additional benefit to current therapeutic options.[3]

Biological Half-Life: 10 hours

[1]. A review of the pharmacological and clinical\nprofile of mirtazapine. CNS Drug Rev, 2001. 7(3): p. 249-64.

[2]. Interaction between enantiomers of mianserin and ORG3770 at\n5-HT3 receptors in cultured mouse neuroblastoma\ncells.Neuropharmacology.1994 Mar-Apr;33(3-4):501-7.

[3].Racemic\nintrathecal mirtazapine but not its enantiomers acts anti-neuropathic\nafter chronic constriction injury in rats. Brain Res Bull. 2009 Apr\n6;79(1):63-8.

Esmirtazapine, known by the standardized identifier SCH 900265, was under development by Organon to treat insomnia and vasomotor symptoms associated with menopause. Esmirtazapine is the (S)-(+)-enantiomer of mirtazapine and possesses similar overall pharmacology. This includes inverse agonist activity of H1 and 5-HT2 receptors and antagonism of α2-adrenergic receptors. Merck has terminated its internal clinical development program for esmirtazapine as of March 2010.

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A piperazinoazepine tetracyclic compound that enhances the release of NOREPINEPHRINE and SEROTONIN through blockage of presynaptic ALPHA-2 ADRENERGIC RECEPTORS. It also blocks both 5-HT2 and 5-HT3 serotonin receptors and is a potent HISTAMINE H1 RECEPTOR antagonist. It is used for the treatment of depression, and may also be useful for the treatment of anxiety disorders.

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The novel antidepressant mirtazapine has a dual mode of action. It is a noradrenergic and specific serotonergic antidepressant (NaSSA) that acts by antagonizing the adrenergic alpha2-autoreceptors and alpha2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission. This dual mode of action may conceivably be responsible for mirtazapine's rapid onset of action. Mirtazapine is extensively metabolized in the liver. The cytochrome (CYP) P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4 are mainly responsible for its metabolism. Using once daily dosing, steady-state concentrations are reached after 4 days in adults and 6 days in the elderly. In vitro studies suggest that mirtazapine is unlikely to cause clinically significant drug-drug interactions. Dry mouth, sedation, and increases in appetite and body weight are the most common adverse effects. In contrast to selective serotonin reuptake inhibitors (SSRIs), mirtazapine has no sexual side effects. The antidepressant efficacy of mirtazapine was established in several placebo-controlled trials. In major depression, its efficacy is comparable to that of amitriptyline, clomipramine, doxepin, fluoxetine, paroxetine, citalopram, or venlafaxine. Mirtazapine also appears to be useful in patients suffering from depression comorbid with anxiety symptoms and sleep disturbance. It seems to be safe and effective during long-term use.[2]

C17H19N3

265.36

265.157

C, 76.95; H, 7.22; N, 15.84

61337-87-9

Mirtazapine;85650-52-8;(S)-Mirtazapine-d3;(R)-Mirtazapine;61364-37-2;Mirtazapine-d3;1216678-68-0;(R)-Mirtazapine-d3; 1448014-35-4 (HCl); 680993-85-5; 61337-87-9

3085218

Typically exists as Off-white to light yellow solid at room temperature

1.2±0.1 g/cm3

432.4±45.0 °C at 760 mmHg

215.3±28.7 °C

0.0±1.0 mmHg at 25°C

1.668

2.75

19.37

N12C3C(=CC=CN=3)CC3C=CC=CC=3[C@H]1CN(C)CC2

RONZAEMNMFQXRA-MRXNPFEDSA-N

InChI=1S/C17H19N3/c1-19-9-10-20-16(12-19)15-7-3-2-5-13(15)11-14-6-4-8-18-17(14)20/h2-8,16H,9-12H2,1H3/t16-/m1/s1

(7S)-5-methyl-2,5,19-triazatetracyclo[13.4.0.02,7.08,13]nonadeca-1(15),8,10,12,16,18-hexaene

Esmirtazapine; (S)-Mirtazapine; 61337-87-9; (+)-Mirtazapine; S-Mirtazapine; Esmirtazapine [INN]; (s)-org 3770; (s)-6-azamianserin; ORG 50081; ORG-50081; ORG50081

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;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
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。