BRL-15572 HCl   中文名称: BRL-15572

5-HT1D ( pKi = 7.9 ); 5-HT1A ( pKi = 7.7 ); 5-HT2B ( pKi = 7.4 ); 5-HT2A ( pKi = 6.6 ); 5-HT7 ( pKi = 6.3 )

BRL-15572 对 CHO 细胞中产生的 h5-HT1D 受体的亲和力比 5-HT1B 受体高 60 倍 (pKi=7.9) [1]。 BRL-15572 (0.1 nM–10 μM) 可刺激表达 h5-HT1B 和 h5-HT1D 受体的 CHO 细胞膜中的 [35S]GTPγS 结合 [1]。

在福尔马林试验中，BRL-15572抑制(-)-表儿茶素引起的镇痛作用[2]。腹腔注射BRL-15572（0.3-100.0 mg/kg）是惰性的，BRL-15572（0.1-10 mg/kg）对豚鼠的体温没有影响[3]。

尽管h5-HT1B和h5-HT1D受体氨基酸序列之间只有适度的同源性，但这些受体显示出非常相似的药理学。迄今为止，很少有化合物能区分这些受体亚型和那些具有一定选择性的化合物，如酮色林，对其他5-HT受体亚型具有更大的亲和力。我们现在报告了两种化合物，SB-216641（N-[3-（2-二甲氨基）乙氧基-4-甲氧基苯基]-2'-甲基-4'-（5-甲基-1,2,4-恶二唑-3-基）-（1,1'-联苯）-4-甲酰胺）和BRL-155723-[4-（3-氯苯基）哌嗪-1-基]-1,1-二苯基-2-丙醇），它们分别对h5-HT1B和h5-HT1D受体显示出高亲和力和选择性。在CHO细胞中表达的人受体的受体结合研究中，SB-216641对h5-HT1B受体具有高亲和力（pKi=9.0），对h5-HT1D受体的亲和力低25倍。相比之下，BRL-15572对h5-HT1D（pKi=7.9）的亲和力比5-HT1B受体高60倍。在豚鼠纹状体的天然组织5-HT1B受体上测定了这些化合物的类似亲和力。在[35S]GTPγS结合试验和重组h5-HT1B和h5-HT1D受体上的cAMP积累试验中测量了SB-216641和BRL-15572的功能活性。这两种化合物在这些高受体表达系统中都是部分激动剂，其效力和选择性与其受体结合亲和力相关。在cAMP积累测定中，化合物的pK（B）测量结果再次与受体结合亲和力相关（SB-216641，pK（B）=9.3和7.3BRL-15572，pK（B）=<6，h5-HT1B和h5-HT1D受体分别为7.1）。这些化合物将成为表征5-HT1B和5-HT1D受体介导反应的有用药理学试剂[1]。

The aim of this study was to investigate the antinociceptive potential of (-)-epicatechin and the possible mechanisms of action involved in its antinociceptive effect. The carrageenan and formalin tests were used as inflammatory pain models. A plethysmometer was used to measure inflammation and L5/L6 spinal nerve ligation as a neuropathic pain model. Oral (-)-epicatechin reduced carrageenan-induced inflammation and nociception by about 59 and 73%, respectively, and reduced formalin- induced and nerve injury-induced nociception by about 86 and 43%, respectively. (-)-Epicatechin-induced antinociception in the formalin test was prevented by the intraperitoneal administration of antagonists: methiothepin (5-HT1/5 receptor), WAY-100635 (5-HT1A receptor), SB-224289 (5-HT1B receptor), BRL-15572 (5-HT1D receptor), SB-699551 (5-HT5A receptor), naloxone (opioid receptor), CTAP (μ opioid receptor), nor-binaltorphimine (κ opioid receptor), and 7-benzylidenenaltrexone (δ1 opioid receptor). The effect of (-)-epicatechin was also prevented by the intraperitoneal administration of L-NAME [nitric oxide (NO) synthase inhibitor], 7-nitroindazole (neuronal NO synthase inhibitor), ODQ (guanylyl cyclase inhibitor), glibenclamide (ATP-sensitive K channel blocker), 4-aminopyridine (voltage-dependent K channel blocker), and iberiotoxin (large-conductance Ca-activated K channel blocker), but not by amiloride (acid sensing ion channel blocker). The data suggest that (-)-epicatechin exerts its antinociceptive effects by activation of the NO-cyclic GMP-K channels pathway, 5-HT1A/1B/1D/5A serotonergic receptors, and μ/κ/δ opioid receptors.[2]

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The selective, brain penetrant, 5-HT(1B/D) (formerly 5-HT(1D beta/alpha)) receptor agonist SKF-99101H (3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole hemifumarate) (30 mg/kg i.p.) causes a dose related fall in rectal temperature in guinea pigs which previous studies have shown to be blocked by the non-selective 5-HT(1B/D) receptor antagonist GR-127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1'biphenyl]-4-carboxamide oxalate). The present study shows that the hypothermic response to SKF-99101H is dose-dependently blocked by SB-224289G (1'-methyl-5-(2'-methyl-4'-[(5-methyl-1,2,4-oxadiazol-3-yl)bipheny l-4-yl]carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-pi peridone] hemioxalate) (0.3-10.0 mg/kg p.o.) (ED50 3.62 mg/kg), which is the first compound to be described which is more than 60 fold selective for the 5-HT1B receptor over the 5-HT1D receptor. SB-216641A (N-[3-(2-dimethylamino) ethoxy-4-methoxy-phenyl] 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-car boxamide hydrochloride) (0.6-20.0 mg/kg i.p.), which is somewhat less selective (30 fold) for the 5-HT1B receptor over the 5-HT1D receptor had a similar effect (ED50 4.43 mg/kg). The brain penetrant 5-HT1D selective receptor antagonist, BRL-15572 (4-(3-chlorophenyl)-alpha-(diphenylmethyl)-1-piperazineethanol+ ++ dihydrochloride) (0.3-100.0 mg/kg i.p.) was inactive. When administered alone neither BRL-15572 (0.1-10 mg/kg i.p.) nor SB-224289G (2.2-22 mg/kg p.o.) had an effect on body temperature. These data demonstrate that 5-HT1B (formerly 5-HT(1D beta)) and not 5-HT1D (formerly 5-HT(1D alpha)) receptors mediate the hypothermic response to SKF-99101H (30 mg/kg i.p.) in guinea pigs. The compounds described are useful pharmacological tools for distinguishing responses to 5-HT1B and 5-HT1D receptors.[3]

[1]. SB-216641 and BRL-15572--compounds to pharmacologically discriminate h5-HT1B and h5-HT1D receptors. Naunyn Schmiedebergs Arch Pharmacol. 1997 Sep; 356(3): 312-20.

[2]. Antinociceptive effect of (-)-epicatechin in inflammatory and neuropathic pain in rats. Behav Pharmacol. 2018 Apr; 29(2 and 3-Spec Issue): 270-279.

[3]. Stimulation of 5-HT1B receptors causes hypothermia in the guinea pig. Eur J Pharmacol. 1997 Jul 23; 331(2-3): 169-74.

1. This study investigated how aloxen-induced diabetes affects the regulatory effect of serotonin (5-HT) on vagal nerve stimulation-induced bradycardia in decerebrated rats and analyzed the 5-HT receptor types and/or subtypes involved. 2. Male Wistar rats were induced to develop diabetes by a single subcutaneous injection of aloxen (150 mg/kg). Four weeks later, the rats were anesthetized, pre-injected with atenolol, and then decerebrated. Vagal nerve stimulation (3, 6, and 9 Hz) resulted in a frequency-dependent decrease in heart rate (HR). 3. In diabetic rats, intravenous administration of high doses of 5-HT (100 and 200 μg/kg) enhanced vagal nerve stimulation-induced bradycardia. Similarly, low doses (10 μg/kg) of the 5-HT (1/7) receptor agonist serotonin (5-CT) enhanced vagal nerve-induced bradycardia. However, high doses (50, 100, and 150 μg/kg) of 5-CT attenuated bradycardia. L-694,247 (50 μg/kg), a selective non-rodent 5-HT(1B) and 5-HT(1D) receptor agonist, reproduced the attenuating effect of high-dose 5-CT on vagal-induced bradycardia. The selective 5-HT(1A) receptor agonist 8-hydroxydipropylaminotraline hydrobromide (8-OH-DPAT; 50 μg/kg) reproduced the enhancing effect of low-dose 5-CT on vagal-induced bradycardia. These stimulatory and inhibitory effects on vagal-induced bradycardia were also observed in diabetic rats after administration of exogenous acetylcholine. 4. Administration of the selective 5-HT(2) receptor agonist α-methyl-5-HT (150 μg/kg), the selective 5-HT(3) receptor agonist 1-phenylbiguanide (150 μg/kg), or the selective 5-HT(1B) receptor agonist CGS-12066B (50 μg/kg) did not affect vagal-induced bradycardia in diabetic rats. 5. The enhancement of electrical stimulation-induced bradycardia in diabetic rats induced by 5-CT (10 μg/kg) or 8-OH-DPAT (50 μg/kg) was blocked by the selective 5-HT(2/7) receptor antagonist mesocergoline (1 mg/kg) and the selective 5-HT(1A) receptor antagonist WAY-100,635 (100 μg/kg), respectively. Similarly, pre-administration of the non-selective 5-HT(1) receptor antagonist methiothiapine (0.1 mg/kg) blocked the inhibitory effect of 5-CT (50 μg/kg) on vagal nerve stimulation-induced bradycardia in diabetic rats. The selective 5-HT(1D) receptor antagonist BRL-15572 (2 μg/kg) inhibited the effects of non-rodent 5-HT(1B) and 5-HT(1D) receptor selective agonists L-694,247 (50 μg/kg) on vagal nerve-induced bradycardia. 6. In summary, in this study, experimental diabetes induced changes in the nature of vagal nerve-induced bradycardia and the 5-HT receptor type/subtype. [https://pubmed.ncbi.nlm.nih.gov/17880377/]

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Previous studies have shown that ergotamine induces vasoconstriction of the external carotid artery in vagotomized dogs via 5-HT1B/1D receptors and α2-adrenergic receptors. This study re-analyzed this view using more selective antagonists, alone or in combination. The study included 52 anesthetized dogs, and ultrasound measurements of external carotid artery blood flow were performed. Animals were divided into 13 groups (n=4 per group) and received either intravenous bolus injection of normal saline (0.3 ml/kg; control group) or the following antagonists: SB224289 (300 μg/kg; 5-HT1B receptor antagonist), BRL15572 (300 μg/kg; 5-HT1D receptor antagonist), rauvolidine (300 μg/kg; α2 receptor antagonist), SB224289 + BRL15572 (300 μg/kg each), SB224289 + rauvolidine (300 μg/kg each), BRL15572 + rauvolidine (300 μg/kg each), rauvolidine (300 μg/kg) + prazosin (100 μg/kg; α1 receptor antagonist), SB224289 (300 μg/kg) + prazosin (100 μg/kg; α1 receptor antagonist), or SB224289 (300 μg/kg) + prazosin (100 μg/kg). SB224289 (300 μg/kg) + Rauvolfine (300 μg/kg) + Prazosin (100 μg/kg), SB224289 (300 μg/kg) + Prazosin (100 μg/kg) + BRL44408 (1,000 μg/kg; α2A), SB224289 (300 μg/kg) + Prazosin (100 μg/kg) + Imidoxacin (1,000 μg/kg; α2B), or SB224289 (300 μg/kg) + Prazosin (100 μg/kg) + MK912 (300 μg/kg; α2C). All animals received continuous 1-minute infusions of ergotamine into the internal carotid artery (0.56, 1, 1.8, 3.1, 5.6, 10, and 18 μg/min) according to a cumulative protocol. In animals pretreated with saline, ergotamine dose-dependently reduced external carotid artery blood flow without affecting arterial blood pressure or heart rate. These control responses were unaffected by SB224289, BRL15572, rauvolidine, or combinations of SB224289 + BRL15572, BRL15572 + rauvolidine, rauvolidine + prazosin, SB224289 + prazosin, or SB224289 + prazosin + imidazofloxacin; and were slightly blocked by SB224289 + rauvolidine. SB224289 + rauwolfiain + prazosin, SB224289 + prazosin + BRL44408, or SB224289 + prazosin + MK912 significantly blocked this vasoconstriction. Therefore, ergotamine-induced intracranial selective vasoconstriction in dogs is mainly mediated by 5-HT1B receptors and α2A/2C adrenergic receptor subtypes, while the mediating effect of α1 adrenergic receptors is relatively small. [https://pubmed.ncbi.nlm.nih.gov/15224175/]

C25H29CL3N2O

479.87

478.1345

C, 67.72; H, 6.37; Cl, 15.99; N, 6.32; O, 3.61

1173022-77-9

193611-72-2

9891303

Typically exists as solid at room temperature

580.7ºC at 760 mmHg

305ºC

2.51E-14mmHg at 25°C

5.459

26.71

3

3

6

31

451

0

0

BRL-15,572; BRL 15572 HCl; 193611-72-2; BRL-15572 dihydrochloride; 3-(4-(3-chlorophenyl)piperazin-1-yl)-1,1-diphenylpropan-2-ol dihydrochloride; BRL-15572 (dihydrochloride); BRL-15572 2HCl; BRL 15572; 3-[4-(3-chlorophenyl)piperazin-1-yl]-1,1-diphenylpropan-2-ol;dihydrochloride; 3-[4-(3-chlorophenyl)piperazin-1-yl]-1,1-diphenylpropan-2-ol dihydrochloride; BRL15572

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)

DMSO : ~250 mg/mL (~520.97 mM)
H2O : ~2 mg/mL (~4.17 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.33 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (4.33 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (4.33 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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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。