5-HT₆ Receptor ( pKi = 8.92-9.09 )

体外活性：SB-271046 还可有效取代大鼠和猪纹状体和人尾壳膜上的 [125I]-SB-258585，pK 分别为 9.02、8.55 和 8.81。 SB-271046 竞争性拮抗 5-HT 诱导的腺苷酸环化酶活性刺激，pA2 为 8.71。在功能性腺苷酸环化酶测定中发现 SB-271046 是一种竞争性拮抗剂，pA2 为 8.7，这与其结合亲和力非常一致。 SB-271046 对主要人类 P450 酶没有显着的抑制活性。激酶测定：SB271046 Hcl 是一种有效的、选择性的、口服活性的 5-HT6 受体拮抗剂，pKi 为 8.9。 IC50值：8.9(pKi)。 SB 271046盐酸盐是一种磺酰氨基苯甲酸衍生物，已被证明是一种选择性的5-HT6拮抗剂，PKI值为9.02-8.92，6.55，6.55，6.35，6.35，6.35，6.27 , 5.27 和 < 4.99 对于 5-HT6、5-HT1D、5-HT1A、D3、5-HT1B、5-HT1F、α1B、5-HT2C、5-HT2A、D2、5-HT2B、5-HT7、5-分别为 HT4 和 5-HT1E，其选择性比 55 种其他受体、酶和离子通道高 200 倍以上。

在大鼠最大电击癫痫阈值 (MEST) 测试中，SB-271046 在宽剂量范围内可提高癫痫阈值，最小有效剂量为 0.1 mg/kg，口服，最大作用在给药后 4 小时。抗惊厥活性水平与 SB-271046 的血液浓度（EC50 为 0.16 μM）和 Cmax 时的脑浓度（0.01 μM–0.04 μM）密切相关。 SB-271046 具有中等脑渗透性 (10%)，血液清除率较低 (7.7 mL/min/kg)，在大鼠中具有良好的半衰期（4.8 小时），并且具有出色的口服生物利用度 (>80%)。 SB-271046 可使大鼠额叶皮层和背侧海马的细胞外谷氨酸水平分别增加 3 倍和 2 倍，可用于治疗认知和记忆功能障碍。研究发现，在训练 Wistar 大鼠前 30 分钟使用 SB-271046（20 毫克/千克，口服强饲）可显着逆转训练后 6 小时内给予东莨菪碱（0.8 毫克/千克，腹腔注射）产生的遗忘症。与媒介物处理的老年大鼠对照相比，SB-271046 在连续四天的五次连续试验中逐渐显着降低了平台游泳角度和逃避潜伏期。 SB-271046 还改善了任务回忆，通过训练后第 1 天和第 3 天对目标象限的搜索显着增加来衡量。SB-271046（10 mg/kg，皮下注射）产生显着的河豚毒素依赖性细胞外增加大鼠额叶皮质内的谷氨酸和天冬氨酸水平分别达到注射前值的最大值 375.4% 和 215.3%。

SB271046 Hcl 是一种有效的、pKi 为 8.9 的选择性口服 5-HT6 受体拮抗剂。 IC50值：8.9(pKi)。磺酰胺苯并噻吩衍生物 SB 271046 盐酸盐已被证明可作为选择性 5-HT6 拮抗剂，pKi 值为 9.02-8.92、6.55、6.35、6.27、6.05、5.95、5.76、5.73、5.62、5.55、5.41、5.39 、5.27 和 < 4.99（对于 5-HT6、5-HT1D、5-HT1A、D3、5-HT1B、5-HT1F、α1B、5-HT2C、5-HT2A、D2、5-HT2B、5-HT7、5）分别为-HT4和5-HT1E。它的选择性比其他 55 种受体、酶和离子通道高 200 倍以上。

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放射性配体结合[1]
放射性配体结合按照描述进行（Hirst et al., 2000）。简而言之，放射性配体结合是在HeLa细胞的膜上进行的，这些细胞稳定地转染了人5-HT6受体（见上文），纹状体组织来自成年大鼠（Sprague-Dawley, 200-250 g），成年猪（来自当地屠宰场）和人尾状壳核组织（来自年龄在64-76岁，死亡原因非神经系统的未确定患者）。用1 nM [125I]-SB-258585 （Hirst et al., 2000）或2 nM [3H]-LSD在37℃下孵育45分钟。10 μM的甲氧thepin被定义为非特异性结合，并通过Whatman GF/B过滤器快速过滤终止实验。 对于其他5-羟色胺受体的受体选择性研究，Hirst等人（2000）给出了所使用放射配体和测定条件的详细信息。SB-271046还通过CEREP进行了55项结合试验

Male Sprague Dawley rats; Dissolved in 1% methyl cellulose in water; 30 mg/kg; Oral gavage

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Maximal electroshock seizure threshold (MEST) test [1]
Male Sprague Dawley rats (100–150 g), supplied by Charles River, U.K. were housed in groups of 10 at a room temperature of 20–22°C. Animals were maintained on a 12 h light/dark cycle with lights on between 0600 and 1800 h Food nd water were available ad libitum. Drug treatments were evaluated between 1400 and 1800 h alongside time-matched vehicle-treated controls.
The threshold current for electroshock-induced tonic hindlimb extensor seizure was determined using a Hugo Sachs Electronik stimulator, which delivered an adjustable constant current (1–300 mA) of 0.3 s duration, 50 Hz, sinewave form, via corneal electrodes. The stimulus intensity was varied, from a typical baseline of 25 mA, by an ‘up and down' method of shock titration (see Upton et al., 1997, for details). Data generated from treatment groups of n=11–14 were used to calculate the seizure threshold (current producing tonic hindlimb extensor seizure in 50% of animals)±s.e. values according to the method of Kimball et al. (1957). Elevation of seizure threshold is indicative of an anticonvulsant effect whereas a reduction in seizure threshold is indicative of proconvulsant activity. The effects of the selective 5-HT6 receptor antagonists, SB-271046 (0.1–30 mg kg−1 p.o., 4 h pre-test), SB-258510 (10 mg kg−1 p.o., 2–6 h pre-test) (Bromidge et al., 1999) and Ro 04-6790 (0.3–30 mg kg−1 i.p., 1 h pre-test) (Sleight et al., 1998), on seizure threshold were determined. The doses of Ro 04-6790 selected for this study cover the range previously reported to evoke a number of behavioural effects in rats (Sleight et al., 1998; Bentley et al., 1999). SB-271046 and SB-258510 were suspended in 1% methyl cellulose in water and Ro 04-6790 was dispersed in saline. A 1 ml kg−1 dose volume was used for all treatments and doses are expressed as free base.
In order to evaluate the relationship between the level of anticonvulsant activity achieved and blood concentration, the duration of action of a high submaximal dose (10 mg kg−1 p.o.) of SB-271046 in the rat MEST test was evaluated in detail over a 24 h period. Following the conclusion of this study, whole brain and blood samples were taken from randomly selected animals (n=5) at 13 different timepoints. Samples were assayed for SB-271046 using a method based on protein precipitation with acetonitrile, followed by LC/MS/MS analysis employing positive-ion electrospray ionization, with a lowest limit of quantification (LLQ) of 0.01 μM.

[1]. Characterization of SB-271046: a potent, selective and orally active 5-HT(6) receptor antagonist. Br J Pharmacol. 2000 Aug;130(7):1606-12.

SB-271046, potently displaced [(3)H]-LSD and [(125)I]-SB-258585 from human 5-HT(6) receptors recombinantly expressed in HeLa cells in vitro (pK(i) 8.92 and 9.09 respectively). SB-271046 also displaced [(125)I]-SB-258585 from human caudate putamen and rat and pig striatum membranes (pK(i) 8.81, 9.02 and 8.55 respectively). SB-271046 was over 200 fold selective for the 5-HT(6) receptor vs. 55 other receptors, binding sites and ion channels. In functional studies on human 5-HT(6) receptors SB-271046 competitively antagonized 5-HT-induced stimulation of adenylyl cyclase activity with a pA(2) of 8.71. SB-271046 produced an increase in seizure threshold over a wide-dose range in the rat maximal electroshock seizure threshold (MEST) test, with a minimum effective dose of < or =0.1 mg kg(-1) p.o. and maximum effect at 4 h post-dose. The level of anticonvulsant activity achieved correlated well with the blood concentrations of SB-271046 (EC(50) of 0.16 microM) and brain concentrations of 0.01-0.04 microM at C(max). These data, together with the observed anticonvulsant activity of other selective 5-HT(6) receptor antagonists, SB-258510 (10 mg kg(-1), 2-6 h pre-test) and Ro 04-6790 (1-30 mg kg(-1), 1 h pre-test), in the rat MEST test, suggest that the anticonvulsant properties of SB-271046 are likely to be mediated by 5-HT(6) receptors. Overall, these studies demonstrate that SB-271046 is a potent and selective 5-HT(6) receptor antagonist and is orally active in the rat MEST test. SB-271046 represents a valuable tool for evaluating the in vivo central function of 5-HT(6) receptors. [1]

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The present study shows that SB-271046 produces potent and long-lasting anticonvulsant activity in the rat MEST test, a model of previously reported utility for studying the role of serotonergic pathways in seizure regulation (e.g. Upton et al., 1998). Since SB-271046 is a very selective 5-HT6 receptor antagonist (Bromidge et al., 1999; Routledge et al., 1999), the anticonvulsant properties of SB-271046 are likely to be mediated by blockade of 5-HT6 receptors. This is further supported by the demonstrated close correlation between the pharmacokinetic and pharmacodynamic profiles of the compound and the presently observed anticonvulsant activity of other selective 5-HT6 receptor antagonists, SB-258510 (Bromidge et al., 1999; pKi at human 5-HT6 receptor 9.2) and the chemically distinct agent Ro 04-6790 (Sleight et al., 1998). Overall, these data suggest that the MEST test may provide a robust model of in vivo 5-HT6 receptor function, and also illustrate that SB-271046 is a potent and orally active 5-HT6 receptor antagonist. However, the magnitude of these anti-seizure effects was modest in comparison to that of known anti-epileptic drugs For example, using identical test conditions, agents such as carbamazepine can elevate seizure threshold by >1200% (Upton et al., 1997) as compared to the maximum increase of only 132 and 166% produced by SB-258510 and SB-271046, respectively. This low level of anticonvulsant efficacy associated with 5-HT6 receptor blockade probably contributes to the apparent lack of dose-dependency for SB-271046, SB-258510 and Ro 04-6790 in the MEST test, since the anticonvulsant activity of SB-271046 is clearly related to the level of exposure in blood. Therefore, the relevance of this observation to the possible clinical utility of SB-271046 in the treatment of epilepsy is, at this stage, unclear. Taken together, these data demonstrate that SB-271046 is a potent, selective and orally active 5-HT6 receptor antagonist. This compound provides a useful tool for further elucidating the physiological function of 5-HT6 receptors in vivo. [1]

C20H22CLN3O3S2

451.99

487.056

209481-20-9

SB 271046 Hydrochloride; 209481-24-3

5312149

Typically exists as solid at room temperature

1.400

664.3ºC at 760 mmHg

240-241℃ (DEC.)

355.5ºC

6.431

107.29

2

7

5

29

656

0

CC1=C(SC2=C1C=C(C=C2)Cl)S(=O)(=O)NC3=CC(=C(C=C3)OC)N4CCNCC4

LOCQRDBFWSXQQI-UHFFFAOYSA-N

InChI=1S/C20H22ClN3O3S2/c1-13-16-11-14(21)3-6-19(16)28-20(13)29(25,26)23-15-4-5-18(27-2)17(12-15)24-9-7-22-8-10-24/h3-6,11-12,22-23H,7-10H2,1-2H3

5-chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl-1-benzothiophene-2-sulfonamide

SB-271046; SB 271046; SB271046; 209481-20-9; Sb 271046; SB-271046; SB271046; 5-chloro-N-(4-methoxy-3-(piperazin-1-yl)phenyl)-3-methylbenzo[b]thiophene-2-sulfonamide; 5-chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl-1-benzothiophene-2-sulfonamide; L3SK5KX24S; Benzo[b]thiophene-2-sulfonamide, 5-chloro-N-[4-methoxy-3-(1-piperazinyl)phenyl]-3-methyl-; SB-271046 HCl; SB-271046 hydrochloride

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)

DMSO: ~40 mg/mL (~81.9 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL