(R)-SKF-81297 hydrobromide

Dopamine D1 receptor

在D1HEK293细胞中，全D1受体激动剂SKF-81297在内源性G（q/11）偶联毒蕈碱或嘌呤能受体“启动”后引起Ca(2+)(i)的剂量依赖性增加。SKF-81297的作用可被福斯克林或8-Br-cAMP模拟。此外，霍乱毒素和camp依赖性蛋白激酶（PKA）抑制剂KT5720和H89以及thapsigargin可以消除D1受体引起的Ca（2+）瞬态。去除启动激动剂和用磷脂酶C抑制剂U73122处理也阻断了 SKF-81297-诱发的反应。D1R激动剂不会刺激IP(3)的产生，但用D1R激动剂预处理细胞会增强G(q)连接受体激动剂对细胞内Ca（2+）储存的动员。在神经元中，SKF-81297和部分D1受体激动剂SKF83959在G（q/11）偶联代谢型谷氨酸受体（mGluR）刺激下促进Ca（2+）振荡。两种D1R激动剂对mglur诱发的Ca（2+）反应的影响均依赖于PKA。总之，这些数据表明，多巴胺D1R激活和随后的cAMP生成动态调节了IP(3)介导的细胞内Ca（2+）储存动员的效率和时间。［３］

在 MPTP 损伤的猴子中，SKF-81297（0.05-0.3 mg/kg，肌肉注射一次）可促进运动活动[1]。所谓的选择性，高效多巴胺D1受体激动剂SKF-81297 (0.05-0.3 mg/kg i.m)，诱导旋转行为远离病变，并刺激单侧（左侧）1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）损伤的恒河猴（Macaca mulatta）使用优势右手。SKF-81297的作用可被多巴胺D1受体拮抗剂SCH 23390 （0.05 mg/kg）完全阻断，但不能被多巴胺D2受体拮抗剂remoxipride （1 mg/kg）完全阻断，与选择性多巴胺D2受体激动剂LY 171555 （0.01 mg/kg）诱导的作用相似。这些结果表明，当使用高效选择性多巴胺D1受体激动剂刺激帕金森病非人灵长类动物模型时，多巴胺D1受体对运动行为具有功能性刺激作用。[1]

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前额叶皮质（PFC） GABAA能神经传递的缺陷与精神分裂症和其他疾病的认知障碍有关，PFC GABAA传递的药物减少会破坏包括工作和空间记忆在内的过程。这为研究能够中和gaba能功能障碍的化合物是否可以改善这些认知缺陷提供了机会。PFC多巴胺（DA） D1受体的激活增强了GABA的传递，这增加了直接或间接的DA D1受体激动剂在逆转工作记忆和其他形式的认知缺陷方面有效的可能性。为了验证这一点，在PFC输注GABAA拮抗剂bicuculline （50 ng）和评估空间工作和参考记忆功能之前，对雄性大鼠进行了两种增强PFC D1信号传导的药物预处理。中等剂量的全D1激动剂SKF-81297 (0.1 mg/kg)完全逆转延迟反应任务中评估的PFC GABA功能减退引起的工作记忆缺陷，而低剂量和高剂量（分别为0.05和0.3 mg/kg）与轻度改善或有害作用相关。四氢原小檗碱d-戈瓦定（0.5或1.0 mg/kg）是一种已知可以选择性地促进PFC中DA释放的合成化合物，它也显著改善了PFC GABAA拮抗诱导的延迟反应工作记忆功能。此外，在放射状迷宫任务中，两种药物的最佳剂量均可部分恢复PFC GABA功能减退引起的参考和短期空间记忆障碍。这些发现表明，通过对DA D1受体的作用来调节PFC DA信号是一种有希望的治疗策略，可以治疗精神疾病中观察到的工作记忆和其他认知障碍，包括那些原因超出DA功能障碍的疾病。[2]

Animal/Disease Models: Four male rhesus monkeys (Macaca mulatta, 7.0-11.3 kg)[1]
Doses: 0.05-0.3 mg/kg
Route of Administration: intramuscular (im) injection, once
Experimental Results: Dramatically increased rotational behavior and right-sided hand use in unilateral MPTP-lesioned rhesus monkeys.

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Drugs, microinfusion procedures and experimental design [2]
Fig. 1 shows a timeline and details of the experimental design. Once a rat achieved criterion performance on a respective task, it received the first of four drug test days that entailed i.p. injection of a drug/vehicle and intra-PFC infusions of the GABAA receptor antagonist bicuculline methbromide (BIC; 50 ng in 0.5 μl) or saline vehicle, using procedures described previously (Auger and Floresco, 2015, Auger and Floresco, 2017). The drugs and doses used for i.p. treatment were the D1 receptor agonist SKF-81297 (SKF) (0.05, 0.1 and 0.3 mg/kg, i.p.) or d-Gov (0.5 and 1.0 mg/kg, i.p.), both of which were dissolved in saline. The four drug test conditions were (I) saline (SAL) i.p. injection-PFC SAL infusion, (“control treatment”), (II) SAL i.p.- PFC BIC infusion, (III) drug i.p. injection-PFC SAL infusion, (IV) drug i.p. injection- PFC BIC infusion. Separate groups of rats were used for each dose of the i.p.-administered drug to minimize the number of intracranial BIC infusions each animal would receive, meaning that each animal within a particular group received the same drug and dosage on both i.p. drug test days. The order of treatments was counter-balanced across animals. Animals were re-trained between test sessions until they re-achieved criterion performance for at least 2 consecutive days, at which point they received the next treatment day. The doses of SKF (Nikiforuk, 2012) and d-Gov (Lapish et al., 2012, Lapish et al., 2014) were selected from previous studies demonstrating improvements in cognition, and we have shown that the 50 ng dose of BIC impairs performance on these tasks without inducing seizures or other non-specific behavioral abnormalities (Auger and Floresco, 2015, Auger and Floresco, 2017, Auger et al., 2017, Auger et al., 2019, Enomoto et al., 2011). For the radial maze experiments, we tested the effects of a single dose of SFK and d-Gov that was shown to be most effective in the DNMTP experiments.

[1]. The selective dopamine D1 receptor agonist, SKF 81297, stimulates motor behaviour of MPTP-lesioned monkeys. Eur J Pharmacol. 1993 Apr 22;235(1):143-7.

[2]. Amelioration of cognitive impairments induced by GABA hypofunction in the male rat prefrontal cortex by direct and indirect dopamine D1 agonists SKF-81297 and d-Govadine. Neuropharmacology. 2020 Jan 1;162:107844.

[3]. A crucial role for cAMP and protein kinase A in D1 dopamine receptor regulated intracellular calcium transients. Neurosignals. 2008;16(2-3):112-23.

9-chloro-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol is a benzazepine.

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D1-like dopamine receptors stimulate Ca(2+) transients in neurons but the effector coupling and signaling mechanisms underlying these responses have not been elucidated. Here we investigated potential mechanisms using both HEK 293 cells that stably express D1 receptors (D1HEK293) and hippocampal neurons in culture. [3]
The present data highlight the therapeutic potential of d-Gov and other D1 agonists for treatment of cognitive impairment in schizophrenia and other psychiatric disorders. In particular, the findings indicate that modulation of mesocortical DA transmission via D1 receptor activation may be viable approach for mitigating cognitive deficits that originate from pathophysiological alterations that extend beyond changes in DA function, such as deficient GABAergic transmission. Therefore, it will be of considerable interest to investigate whether these compounds have utility in reversing the effects of other relevant neural alterations, particularly on other domains of cognition or behavior relevant to positive and negative symptomatology of schizophrenia.[3]

C16H16CLNO2.HBR

370.67

369.01312

C, 66.32; H, 5.57; Cl, 12.23; N, 4.83; O, 11.04

253446-15-0

Typically exists as solids at room temperature

C1=CC=C(C=C1)[C@H]2CNCCC3=C(C(=C(C=C32)O)O)Cl.Br

(R)-SKF-81297; 71636-61-8; (R)-SKF81297; Skf-81297; SKF 81297; SK&F 81297; 6-Chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine-7,8-diol; SKF81297; 1H-3-Benzazepine-7,8-diol,6-chloro-2,3,4,5-tetrahydro-1-phenyl-; 9-chloro-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol;

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。