SB 206553   中文名称: 5-甲基-1-(3-吡啶羰基)-1,2,3,5-四氢吡咯并[2,3-f]吲哚

pKi: 5.6 nM (5-HT2A), 7.7 nM (5-HT2B) and 7.8 nM (5-HT2C)[1].

SB 206553（5-甲基-1-（3-吡啶基氨基甲酰基）-1,2,3,5-四氢吡咯并[2,3-f]吲哚）对HEK 293细胞中表达的克隆人5-HT2C受体和大鼠胃底制剂中测定的5-HT2B受体（pA2 8.9）显示出高亲和力（pK1 7.9）。SB 206553对HEK 293细胞中表达的克隆人5-HT2A受体（pK1 5.8）和各种其他神经递质受体（pK1<6）具有低亲和力。[3]
SB 206553似乎是表达人5-HT2C受体（pKB 9.0）的HEK 293细胞中5-HT刺激的磷酸肌醇水解的可克服拮抗剂。[3]

在相似的剂量下（2-20mg kg−1，口服），SB 206553在大鼠社交互动测试中增加了总互动得分，在大鼠盖勒-塞弗冲突测试中提高了惩罚反应。这些效果与具有抗焦虑特性是一致的。[3]
SB 206553在稍高剂量（口服15和20 mg kg−1）的狨猴焦虑冲突模型中也增加了抑制反应，但也减少了未抑制反应。[3]
这些结果表明，SB 206553是一种强效的混合5-HT2C/5HT2B受体拮抗剂，对5-HT2A和所有其他研究部位具有选择性，并具有抗焦虑样特性。[3]

SB 206553 (SB206), a 5-HT2C inverse agonist, was dissolved in 1 % lactic acid in deionized water and injected ip (1.0, 5.0, and 10.0 mg/kg). Serotonin2C ligands were administered in volumes of 1.0 ml/kg with the exception of 10.0 mg/kg SB206, which was administered at 2 ml/kg (from a 5.0 mg/ml stock solution). All drugs were administered as the base. pKi values of SDZ, SB242 and SB206 for 5-HT2 receptor subtypes are provided in Table 1. [1]

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Cue reactivity testing[1]
Rats were tested for CR after a 30 min pretreatment of 0.1, 0.3, 1.0 mg/kg SDZ and vehicle (treatment group 1) or 1.0, 5.0, 10.0 mg/kg SB 206553 (SB206), and vehicle (group 2). The 5-HT2C receptor antagonist, SB242, was tested against the 5-HT2C receptor inverse agonist SB 206553 (SB206) in the same rats, wherein SB242 (3.0 mg/kg ip) was administered 45 min, and SB206 (5.0 or 10.0 mg/kg ip) was administered 30 min, prior to the onset of CR testing. Dose order was randomized for all treatment groups. Doses of SB206 and SB242 were guided by literature demonstrating significant neurochemical effects in the nucleus accumbens. Doses of SDZ were selected based on reports revealing an enhancement of the interoceptive cues of cocaine and cocaine-evoked motor activity in naïve rats. [1]

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Motor assessments[1]
A subset of rats tested for CR dose–response assessments was used to determine the motor effects of SDZ (1.0 mg/kg ip) and SB 206553 (SB206) (5.0 and 10.0 mg/kg ip) in the presence and absence of meth (1.0 mg/kg ip). For this study, rats were withdrawn from meth and remained in their home cages during protocol days 28–32 and received no treatment (refer to Figure 1). After this 5 day period, rats were tested for motor activity for 3 consecutive days (days 33–35). All motor assessments were conducted using automated small animal activity boxes equipped with two banks of photobeams positioned at different heights to characterize motor activity in three dimensional space. Rats were habituated to activity chambers for 1 hr prior to each motor test. On day 33, rats were administered 1 ml/kg of the respective vehicle for each test drug (rats for effects of SDZ were administered saline and rats tested for SB 206553 (SB206)-induced effects were administered 1 % lactic acid in deionized water). The injected rats were immediately returned to motor boxes for 1 hr after which rats were injected with either SDZ (1.0 mg/kg), or SB 206553 (SB206) (5.0 or 10.0 mg/kg) and behavior was recorded for an additional 1 hr. Motor data collected 30 min post-injection were subsequently analyzed; this time frame reflected the one that was relevant to CR behaviors. On day 34, rats were administered a 30 min pretreatment of vehicle (saline or 1 % lactic acid), then administered 1 mg/kg meth (ip) and behavior recorded for 1 hr. On day 35, the procedure from day 34 was repeated using SDZ (1.0 mg/kg), or SB 206553 (SB206) (5.0 or 10.0 mg/kg) (ip) instead of respective vehicles. Peak meth effects occurred 15 min post meth injection; meth-evoked motor activity was therefore analyzed for the last 45 min of testing (i.e., 15 min post meth injection). Horizontal activity (number of beam breaks in the horizontal plane), vertical activity (number of beam breaks in the vertical plane indicating rearing-like behavior), and total distance (cm traversed within the chamber) were recorded. These assessments provide a reliable index of overall motor patterns evoked by this dose of meth. Stereotypy (rapid, repetitive behaviors) is a prominent component of meth-induced motor activity; therefore, stereotypy number (the number of beam breaks repetitively disrupted) also was analyzed for meth-evoked motor activity. Rats tested for effects of SDZ on motor function were also tested for SDZ effects on CR; similarly, rats tested for effects of SB 206553 (SB206)on motor function had prior exposure to SB 206553 (SB206) during CR assessments.

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Like mirtazapine, pretreatment with SB 206553 (SB206) (1.0, 5.0, and 10.0 mg/kg), attenuated meth-seeking. In contrast, the antagonists, SDZ Ser 082 (0.1, 0.3, and 1.0 mg/kg) and SB 242084 (3.0 mg/kg) had no effect on cue reactivity (CR). SB 242084 (3.0 mg/kg) failed to attenuate the effects of 5.0 and 10 mg/kg SB 206553 on CR. Motor function was largely unaltered by the 5-HT2C ligands; however, SB 206553 (SB206), at the highest dose tested (10.0 mg/kg), attenuated meth-induced rearing behavior.
Conclusions: The lack of effect by 5-HT2C antagonists suggests that meth-seeking and meth-evoked motor activity are independent of endogenous 5-HT acting at 5-HT2C receptors. While SB 206553 (SB206) dramatically impacted meth-evoked behaviors it is unclear whether the observed effects were 5-HT2C receptor mediated. Thus, SB 206553 deserves further attention in the study of psychostimulant abuse disorders.[1]

[1].SB 206553, a putative 5-HT2C inverse agonist, attenuates methamphetamine-seeking in rats. BMC Neurosci. 2012 Jun 14;13:65.

[2].5-Methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole: a novel 5-HT2C/5-HT2B receptor antagonist with improved affinity, selectivity, and oral activity. J Med Chem. 1995 Jul 7;38(14):2524-30.

SB 206553 (SB206) is a pyrroloindole.
Background: Methamphetamine (meth) dependence presents a substantial socioeconomic burden. Despite the need, there is no FDA-approved pharmacotherapy for psychostimulant dependence. We consider 5-HT2C receptors as viable therapeutic targets. We recently revealed that the atypical antidepressant, mirtazapine, attenuates meth-seeking in a rodent model of human substance abuse. Mirtazapine historically has been considered to be an antagonist at 5-HT2C receptors, but more recently shown to exhibit inverse agonism at constitutively active 5-HT2C receptors. To help distinguish the roles for antagonism vs. inverse agonism, here we explored the ability of a more selective 5-HT2C inverse agonist, SB 206553 (SB206) to attenuate meth-seeking behavior, and compared its effects to those obtained with 5-HT2C antagonists, SDZ Ser 082 and SB 242084. To do so, rats were trained to self-administer meth and tested for seeking-like behavior in cue reactivity sessions consisting of contingently presenting meth-associated cues without meth reinforcement. We also explored motor function to determine the influence of SB 206553 and SDZ Ser 082 on motor activity in the presence and absence of meth. Results: Like mirtazapine, pretreatment with SB 206553 (1.0, 5.0, and 10.0 mg/kg), attenuated meth-seeking. In contrast, the antagonists, SDZ Ser 082 (0.1, 0.3, and 1.0 mg/kg) and SB 242084 (3.0 mg/kg) had no effect on cue reactivity (CR). SB 242084 (3.0 mg/kg) failed to attenuate the effects of 5.0 and 10 mg/kg SB 206553 on CR. Motor function was largely unaltered by the 5-HT2C ligands; however, SB 206553, at the highest dose tested (10.0 mg/kg), attenuated meth-induced rearing behavior. Conclusions: The lack of effect by 5-HT2C antagonists suggests that meth-seeking and meth-evoked motor activity are independent of endogenous 5-HT acting at 5-HT2C receptors. While SB 206553 dramatically impacted meth-evoked behaviors it is unclear whether the observed effects were 5-HT2C receptor mediated. Thus, SB 206553 deserves further attention in the study of psychostimulant abuse disorders.[1]

C17H16N4O

292.132

158942-04-2

5163

Typically exists as solid at room temperature

1.33 g/cm3

575.4ºC at 760 mmHg

250 - 252ºC

301.8ºC

3.04E-13mmHg at 25°C

3.305

50.16

1

2

1

22

429

0

QJQORSLQNXDVGE-UHFFFAOYSA-N

InChI=1S/C17H16N4O/c1-20-7-4-12-10-16-13(9-15(12)20)5-8-21(16)17(22)19-14-3-2-6-18-11-14/h2-4,6-7,9-11H,5,8H2,1H3,(H,19,22)

1-methyl-N-pyridin-3-yl-6,7-dihydropyrrolo[2,3-f]indole-5-carboxamide

158942-04-2; SB 206553; SB-206553; 5-Methyl-N-(pyridin-3-yl)-2,3-dihydropyrrolo[2,3-f]indole-1(5H)-carboxamide; Benzo(1,2-b:4,5-b')dipyrrole-1(2H)-carboxamide, 3,5-dihydro-5-methyl-N-3-pyridinyl-; 1-methyl-N-pyridin-3-yl-6,7-dihydropyrrolo[2,3-f]indole-5-carboxamide;

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)

Typically soluble in DMSO (e.g. 10 mM)

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;
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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。