5-HT₇ Receptor ( pKi = 8.3 )

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。

In this study, the effect of the 5-HT(7) receptor antagonist, SB-269970 ((R)-1-[3-hydroxy phenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine), was investigated on 5-HT release in the guinea-pig and rat cortex and the rat dorsal raphe nucleus (DRN), using the techniques of in vitro [(3)H]-5-HT release or fast cyclic voltammetry, respectively. 2. Cortical slices were loaded with [(3)H]-5-HT and release was evoked by electrical stimulation. 5-CT inhibited the evoked release of [(3)H]-5-HT in a concentration-dependent manner. SB-269970 had no significant effect on [(3)H]-5-HT release while the 5-HT(1B) receptor antagonist, SB-224289 significantly potentiated [(3)H]-5-HT release. In addition, SB-269970 was unable to attenuate the 5-CT-induced inhibition of release while SB-224289 produced a rightward shift of the 5-CT response, generating estimated pK(B) values of 7.8 and 7.6 at the guinea-pig and rat terminal 5-HT autoreceptors respectively. 3. Rat DRN slices were electrically stimulated and the evoked 5-HT efflux detected by voltammetric analysis. 8-OH-DPAT inhibited evoked 5-HT efflux and was fully reversed by WAY 100635. SB-269970 had no effect on either 5-HT efflux per se or 8-OH-DPAT-induced inhibition of 5-HT efflux. In addition, 5-CT inhibited 5-HT efflux in a concentration-dependent manner. SB-269970 was unable to attenuate the 5-CT-induced inhibition of 5-HT efflux. 4. In conclusion, we were unable to provide evidence to suggest a 5-HT autoreceptor role for 5-HT(7) receptors. However, investigations with more selective 5-HT(7) receptor agonists are needed to confirm the data reported here.[2]

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

C57BL6/J mice

[1]. Characterization of SB-269970-A, a selective 5-HT(7) receptor antagonist. Br J Pharmacol. 2000 Jun;130(3):539-48.

[2]. The effect of SB-269970, a 5-HT(7) receptor antagonist, on 5-HT release from serotonergic terminals and cell bodies. Br J Pharmacol. 2001 Apr;132(7):1574-80.

[3]. Effects of the selective 5-HT7 receptor antagonist SB-269970 and amisulpride on ketamine-induced schizophrenia-like deficits in rats. PLoS One. 2013 Jun 11;8(6):e66695.

[4]. The serotonin 5-HT7 receptor agonist LP-44 microinjected into the dorsal raphe nucleus suppresses REM sleep in the rat. Behav Brain Res. 2008 Aug 22;191(2):184-9.

3-[[(2R)-2-[2-(4-methyl-1-piperidinyl)ethyl]-1-pyrrolidinyl]sulfonyl]phenol is a sulfonamide.
SB-269970 is an experimental drug developed by GlaxoSmithKline. In the studies performed with this agent, it has been suggested that SB-269970 acts either as a selective antagonist or inverse agonist of the serotonin receptor 7 (5-HT7).

C18H28N2O3S

352.49

352.18

C, 61.33; H, 8.01; N, 7.95; O, 13.62; S, 9.10

201038-74-6

SB-269970 hydrochloride; 261901-57-9

6604889

Solid powder

512.9ºC at 760 mmHg

264ºC

3.87E-11mmHg at 25°C

4.425

69.23

1

5

5

24

497

1

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

HWKROQUZSKPIKQ-MRXNPFEDSA-N

InChI=1S/C18H28N2O3S/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/t16-/m1/s1

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

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)