5-HT₇ Receptor ( pKi = 8.3 nM )

体外活性：SB-269970 抑制豚鼠海马膜中 5-CT 刺激的腺苷酸环化酶活性。 SB-269970（0.03 μM、0.1 μM、0.3 μM 和 1 μM）使 5-CT 浓度-反应曲线产生与浓度相关的右移，而对 5-CT 的最大反应没有显着改变。单独灌注时，SB-269970 (1 μM) 对 5-HT 流出有任何影响。激酶测定：SB269970 是一种 5-HT7 受体拮抗剂，pKi 为 8.3，对其他受体表现出 >50 倍的选择性。

SB-269970（10 mg/kg 和 30 mg/kg）分别显着降低苯丙胺的作用 25% 和 27%，阻断氯胺酮的作用 38%（10 mg/kg）和 30%（30 mg/kg）。公斤）。 SB-269970 显着降低野生型小鼠中苯丙胺诱导的多动症，但对 5-HT7 敲除小鼠没有影响。与对照相比，全身施用 SB-269970 (30 mg/kg) 可显着逆转苯丙胺对 PPI 的破坏，并且本身不会增强 PPI。 SB-269970 显着逆转 MK-801 引起的缺陷，但不能逆转东莨菪碱引起的缺陷。 SB-269970 使 MK-801 诱导的谷氨酸释放正常化，但不能使皮质中的多巴胺释放正常化。 SB-269970（0.5 或 1 mg/kg 的中等剂量）在大鼠 Vogel 饮酒试验、大鼠高架十字迷宫试验和小鼠四板试验中发挥特定的抗焦虑样作用。此外，SB-269970（5 或 10 mg/kg 的中等剂量）在小鼠强迫游泳和悬尾测试中显示出抗抑郁样活性。 SB-269970 在 0.3、1 和 3 μg 剂量下表现出的抗冲突作用弱于地西泮 (40 μg)，而 SB-269970 在 3 和 10 μg 剂量下具有与丙咪嗪相当的显着抗不动作用（0.1 微克）。

SB269970是5-HT7受体的拮抗剂，pKi为8.3，对其他受体表现出>50倍的选择性。新型5-HT（7）受体拮抗剂SB-269970-A能够有效地取代人类5-HT（6（A））（pK（i）8.9+/-0.1）和豚鼠皮质中的5-HT（8）受体（pK，i）8.3+/-0.2）中的[（3）H]-5-CT。5-CT刺激的5-HT（7（a））/HEK293膜（pEC（50）7.5+/-0.1）和SB-269970-a（0.03-1微M）中的腺苷酸环化酶活性抑制了5-CT浓度反应，最大反应没有显著变化。SB-269970-A的pA（2）（8.5+/-0.2）与[（3）H]-5-CT结合研究确定的pK（i）非常一致。SB-269970-A（0.3微M）抑制豚鼠海马膜中5-CT刺激的腺苷酸环化酶活性（pEC（50）为8.4+/-0.2），pK（B）（8.3+/-0.1）与其在人克隆5-HT（7（A））受体上的拮抗效力及其在豚鼠皮层膜上的结合亲和力一致。5-HT（7）受体mRNA在人类下丘脑、杏仁核、丘脑、海马和睾丸中高度表达。SB-269970-A是中枢神经系统渗透剂（大鼠稳态脑：血液比约为0.83:1），但很快从血液中清除（CLb=约140 ml min（-1）kg（-1））[1]。

1. 5-HT(7)受体mRNA和蛋白在5-HT神经元中的存在表明该受体可能作为5-HT自身受体。本研究分别采用体外[(3)H]-5-HT释放法和快速循环伏安法研究了5-HT(7)受体拮抗剂SB-269970 （（R)-1-[3-羟基苯基）磺酰]-2-[2-（4-甲基-1-哌啶基）乙基]吡罗烷）对豚鼠和大鼠皮层和大鼠中颌背核（DRN） 5-HT释放的影响。2. 皮层切片加载[(3)H]-5-羟色胺，电刺激诱发释放。5-CT呈浓度依赖性抑制[(3)H]-5-HT的诱发释放。SB-269970对[(3)H]-5-HT的释放无显著影响，而5-HT（1B）受体拮抗剂SB-224289显著增强[(3)H]-5-HT的释放。此外，SB-269970不能减弱5-CT诱导的释放抑制，而SB-224289使5-CT反应向右移动，在豚鼠和大鼠末端5-HT自受体处分别产生估计的pK(B)值为7.8和7.6。3. 电刺激大鼠DRN切片，用伏安法检测诱发的5-羟色胺外排。8-OH-DPAT抑制诱发的5-HT外排，并被WAY 100635完全逆转。SB-269970对5-HT外排本身和8- oh - dpat诱导的5-HT外排抑制均无影响。此外，5-CT以浓度依赖性的方式抑制5-HT外排。SB-269970不能减弱5- ct诱导的5-HT外排抑制。4. 总之，我们无法提供证据表明5-HT(7)受体具有5-HT自身受体的作用。然而，需要更多选择性5-HT(7)受体激动剂的研究来证实本文报道的数据。[2]

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新型5-HT(7)受体拮抗剂SB-269970-A能有效取代人5-HT(7(a)) （pK(i) 8.9+/-0.1）和豚鼠皮质5-HT(7)受体（pK(i) 8.3+/-0.2）中的[(3)H]-5-CT。5-CT刺激5-HT(7(a))/HEK293膜（pEC(50) 7.5+/-0.1）和SB-269970-A（0.03 - 1微米）腺苷酸环化酶活性，抑制5-CT浓度反应，最大反应无明显变化。SB-269970-A的pA(2)（8.5+/-0.2）与[(3)H]-5-CT结合研究确定的pK(i)非常吻合。5- ct刺激的豚鼠海马膜腺苷酸环化酶活性（pEC（50）为8.4+/-0.2）被SB-269970-A（0.3微米）的pK(B)（8.3+/-0.1）抑制，这与其对人克隆5-HT（7(a)）受体的拮抗剂效力及其在豚鼠皮质膜的结合亲和力很好地一致。5-HT(7)受体mRNA在人类下丘脑、杏仁核、丘脑、海马和睾丸中高表达。

Following a single dose (3 mg kg(-1)) SB-269970 was detectable in rat brain at 30 (87 nM) and 60 min (58 nM). In guinea-pigs, brain levels averaged 31 and 51 nM respectively at 30 and 60 min after dosing, although the compound was undetectable in one of the three animals tested. 5-CT (0.3 mg kg(-1) i.p.) induced hypothermia in guinea-pigs was blocked by SB-269970-A (ED(50) 2.96 mg kg(-1) i.p.) and the non-selective 5-HT(7) receptor antagonist metergoline (0.3 - 3 mg kg(-1) s.c.), suggesting a role for 5-HT(7) receptor stimulation in 5-CT induced hypothermia in guinea-pigs. SB-269970-A (30 mg kg(-1)) administered at the start of the sleep period, significantly reduced time spent in Paradoxical Sleep (PS) during the first 3 h of EEG recording in conscious rats.[1]

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Researchers evaluated the effects of SB-269970, a selective 5-HT7 receptor antagonist, on amphetamine and ketamine-induced hyperactivity and prepulse inhibition (PPI) deficits. In addition, sensorimotor gating function and locomotor activity were evaluated in 5-HT7 knockout mice. Locomotor activity was measured for up to 180 min using an automated infrared photobeam system, and PPI was evaluated in startle chambers. SB-269970 (3, 10 and 30 mg/kg, intraperitoneally) significantly blocked amphetamine [3 mg/kg, subcutaneously (s.c.)] and ketamine (30 mg/kg, s.c.)-induced hyperactivity and reversed amphetamine (10 mg/kg, s.c.)-induced but not ketamine (30 mg/kg, s.c.)-induced PPI deficits, without changing spontaneous locomotor activity and startle amplitude. The largest dose of SB-269970 did not block the effects of amphetamine in 5-HT7 knockout mice. Collectively, these results indicate that blockade of 5-HT7 receptors partially modulates glutamatergic and dopaminergic function and could be clinically useful for the treatment of positive symptoms of schizophrenia.[3]

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Dissolved in saline; 10 mg/kg, 30 mg/kg; i.p.injection

C57BL6/J mice

[1]. Br J Pharmacol . 2000 Jun;130(3):539-48.

[2]. Br J Pharmacol . 2001 Apr;132(7):1574-80.

[3]. Behav Pharmacol . 2008 Mar;19(2):153-9.

[4]. FASEB J, 2009, 23, Meeting Abstract Supplement, 586.6.

[5]. Neuropharmacology . 2006 Sep;51(3):578-86.

[6]. Eur J Pharmacol . 2006 Dec 28;553(1-3):185-90.

The aim of the present study was to examine the effect of the selective 5-HT7 receptor antagonist SB 269970 (0.25-20 mg/kg) in the behavioral tests commonly used for predicting anxiolytic- and antidepressant-like activity. Diazepam and imipramine were used as standard drugs. SB 269970 (in one medium dose of 0.5 or 1 mg/kg) exerted a specific antianxiety-like effect in the Vogel drinking test in rats, in the elevated plus-maze test in rats and in the four-plate test in mice. Moreover, SB 269970 (in one medium dose of 5 or 10 mg/kg) showed antidepressant-like activity in the forced swimming and the tail suspension tests in mice. At the same time, the tested compound at doses of 1-20 mg/kg did not change the spontaneous locomotor activity of mice. The potential anxiolytic and antidepressant effects produced by SB 269970 were weaker than those of the reference drugs employed. It is noteworthy that the active doses of SB 269970 were devoid of any visible motor side-effects. In conclusion, the results of our studies indicate that 5-HT7 receptor antagonists may play a role in the therapy of both anxiety and depression.[5]

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Using conflict drinking and forced swimming tests in rats, we examined the anxiolytic- and the antidepressant-like activity, respectively, of (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]-pyrrolidine (SB 269970), a selective 5-HT(7) receptor antagonist, after its intrahippocampal administration. SB 269970 at doses of 0.3, 1 and 3 mug showed an anticonflict effect which was weaker than that of diazepam (40 mug), whereas SB 269970 at doses of 3 and 10 mug had marked anti-immobility action comparable to that of imipramine (0.1 mug). Importantly, the anxiolytic- and antidepressant-like activity of SB 269970 seemed to be specific, since that agent - when given by the same route in doses effective in either model - affected neither the shock threshold, nor the non-punished water consumption, nor the exploratory activity of rats. The obtained results indicate that the hippocampus is one of the neuroanatomical structures involved in the potential anxiolytic and, in particular, antidepressant activity of SB 269970.[6]

C18H29CLN2O3S

388.95

388.159

C, 55.58; H, 7.52; Cl, 9.11; N, 7.20; O, 12.34; S, 8.24

261901-57-9

SB-269970; 201038-74-6

11957684

White to off-white solid powder

4.425

69.23

2

5

5

25

497

1

OC1=CC=CC(S(=O)(N2[C@@H](CCN3CCC(C)CC3)CCC2)=O)=C1.[H]Cl

XQCJOYZLWFNDIO-PKLMIRHRSA-N

InChI=1S/C18H28N2O3S.ClH/c1-15-7-11-19(12-8-15)13-9-16-4-3-10-20(16)24(22,23)18-6-2-5-17(21)14-18;/h2,5-6,14-16,21H,3-4,7-13H2,1H3;1H/t16-;/m1./s1

3-[(2R)-2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidin-1-yl]sulfonylphenol;hydrochloride

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.43 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 25.0 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 2 中的溶解度: ≥ 2.5 mg/mL (6.43 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 25.0 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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配方 3 中的溶解度: 30% Propylene glycol , 5% Tween 80 , 65% D5W: 30mg/mL

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配方 4 中的溶解度: 10 mg/mL (25.71 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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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。