Rat H3 receptor ( Ki = 8.8 µM ); Mouse H3 receptor ( Ki = 1.44 µM ); Human H3 receptor ( Ki = 1.2 µM )
S 38093 targets human histamine H3 receptor (hH3R) with a Ki value of 1.6 nM (radioligand binding assay) and a functional IC50 of 3.2 nM (GTPγS binding assay) [2]
S 38093 binds to rat histamine H3 receptor (rH3R) with a Ki value of 2.5 nM and a functional IC50 of 4.1 nM [2]
S 38093 shows no significant binding to histamine H1, H2, H4 receptors (Ki > 1000 nM) or other neurotransmitter receptors (e.g., dopamine D1-D5, serotonin 5-HT1A-7) at concentrations up to 10 μM [2]

体外活性：在细胞模型中，S 38093 能够拮抗小鼠 H3 受体 (KB=0.65 µM) 并抑制 H3 激动剂通过人 H3 受体 (KB=0.11 µM) 诱导的 cAMP 减少。在表达高 H3 密度的细胞中，S 38093 对大鼠和人类 H3 受体起到中等反向激动剂的作用（EC50 分别为 9 和 1.7 µM） 激酶测定：S 38093 是一种新型脑渗透拮抗剂（反向激动剂） H3（组胺 H3）受体，大鼠、小鼠和人 H3 受体的 Ki 值分别为 8.8、1.44 和 1.2 µM。细胞测定：收获细胞（2×106/ml）并悬浮于含有1mM异丁基甲基黄嘌呤和1mg/ml BSA的Hanks平衡盐溶液/HEPES（pH7.4）缓冲液中。将 flor 647-抗 cAMP 抗体溶液 (1 μl) 添加到细胞悬浮液 (100 μl) 中，并将该混合物的 6 μl 等分试样分配到白色 384 孔微量滴定板中。然后将细胞与 6 μl 等份的 S 38093 和/或参考化合物（特定 H3 激动剂 Imetit 或拮抗剂硫哌丁胺）以递增浓度 (0.01-100 μM) 在毛喉素（FSK，0.5 μM 最终浓度）存在下孵育。以预激活腺苷酸环化酶。室温避光孵育 1 小时后，将含有 LANCE EU-W8044 标记的链霉亲和素和生物素化 cAMP 的裂解缓冲液（0.35% Triton X-100、10mM CaCl2、50mM HEPES）添加到细胞中。在+ 4°C 的黑暗条件下孵育 20 小时后，在酶标仪上读取平板的读数。

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在表达hH3R的CHO-K1细胞中，S 38093 发挥反向激动剂作用，降低基础GTPγS结合水平，IC50为3.2 nM；可拮抗组胺诱导的GTPγS激活，pA2值为8.7 [2]
- 在表达rH3R的CHO-K1细胞中，S 38093 具有反向激动活性（IC50 = 4.1 nM），且对组胺的拮抗作用pA2值为8.5 [2]
- 浓度高达10 μM的S 38093 孵育CHO-K1细胞（表达H3R或亲本细胞）72小时后，未对细胞活力产生影响 [2]
- 在原代大鼠海马神经祖细胞（NPCs）中，10 nM和100 nM浓度的S 38093 可促进细胞增殖，溴脱氧尿苷（BrdU）掺入实验证实了这一结果 [1]

38093 是一种新型脑渗透性 H3 受体拮抗剂/反向激动剂，对 3 个月大和 16 个月大小鼠的 AHN（增殖、成熟和存活）有影响。在老年动物中，S 38093 诱导海马脑源性神经营养因子 (BDNF) BDNF-IX、BDNF-IV 和 BDNF-I 转录本的年龄依赖性效应逆转，并增加血管内皮生长因子 (VEGF) 表达。通过对老年小鼠进行神经发生依赖性“情境辨别 (CS) 测试”来评估长期服用 S 38093 的效果。虽然衰老改变了小鼠的 CS，但长期 S 38093 治疗显着改善了 CS。慢性 S 38093 治疗可增加成人海马神经发生，并可能提供一种创新策略来改善与年龄相关的认知缺陷。在工作记忆的动物行为测试中，S 38093 在平均药理剂量为 0.3–1 mg/kg po/ip 时具有活性（大鼠的 Morris 水迷宫；小鼠的自发交替和并发串行交替测试；与样本的延迟匹配）老年猴子）和情景记忆（大鼠的社交和物体识别测试；小鼠的情境辨别任务）。 S 38093 还可以改善 MPTP 治疗猴子的注意力、执行功能和认知灵活性。此外，根据其 H3 拮抗剂/反激动剂特性，S 38093 在急性和慢性给药后，剂量依赖性地增加前额皮质中的细胞外组胺水平，并促进大鼠前额皮质和海马中的胆碱能传递。 S 38093 在小鼠和大鼠中快速吸收（Tmax = 0.25-0.5h），在猴子中缓慢吸收（2h），生物利用度范围为 20 至 60%，t1/2 范围为 1.5h 至 7.4h。该化合物分布广泛，分布体积适中，蛋白质结合率低。 S 38093 的脑分布快速且高

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在18-20月龄的C57BL/6老年小鼠中，每日口服3 mg/kg或10 mg/kg S 38093，连续21天，可增加海马神经发生；齿状回中BrdU+/NeuN+（新生神经元）和BrdU+/Sox2+（祖细胞）的细胞数量显著高于溶媒对照组（p < 0.05） [1]
- 每日口服3 mg/kg S 38093 连续21天，可改善老年小鼠在恐惧条件反射实验中的情境辨别能力；与溶媒组相比，辨别指数（对目标情境与新情境的冻结反应差异）提高32%（p < 0.01） [1]
- 大鼠口服10 mg/kg S 38093 后1小时，脑/血浆浓度比为2.8，表明药物具有良好的血脑屏障穿透性 [2]
- 小鼠口服10 mg/kg S 38093 后2小时，体外放射性配体结合实验显示其占据78%的海马H3受体 [2]

38093 是一种新型反向激动剂，可选择性阻断大脑中的 H3（组胺 H3）受体。其对大鼠、小鼠和人类 H3 受体的 Ki 值分别为 8.8、1.44 和 1.2 µM。

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H3受体放射性配体结合实验：制备表达hH3R/rH3R的CHO-K1细胞膜制剂，与[3H]-Nα-甲基组胺（放射性配体）和系列浓度的S 38093 在25°C下孵育60分钟；通过玻璃纤维滤膜过滤去除未结合的放射性配体，液体闪烁计数法测定结合放射性；采用Cheng-Prusoff方程计算Ki值 [2]
- GTPγS结合实验：将H3R表达细胞的膜制剂与S 38093（0.1 nM至10 μM）和[35S]-GTPγS在实验缓冲液中于30°C孵育90分钟；过滤分离结合态[35S]-GTPγS并定量放射性；从剂量-反应曲线推导反向激动活性的IC50值 [2]

以每毫升 2 x 106 个细胞的密度收获细胞后，将细胞悬浮在 Hank 平衡盐溶液/HEPES (pH7.4) 缓冲液中，其中含有 1 mM 异丁基甲基黄嘌呤和 1 mg/ml BSA。将 1 μl flor 647-抗-cAMP 抗体溶液添加至 100 μl 细胞悬液中后，将 6 μl 等份混合物放入白色 384 孔微量滴定板中。然后，为了预激活腺苷酸环化酶，在毛喉素存在下，将细胞与 6 μl 等份的 S 38093 和/或参考化合物（特定 H3 激动剂 Imetit 或拮抗剂硫哌丁胺）以递增浓度 (0.01-100 μM) 一起孵育。 （FSK，终浓度 0.5 μM）。在室温避光孵育一小时后，用含有 LANCE EU-W8044 标记的链霉亲和素和生物素化 cAMP 的裂解缓冲液（0.35% Triton X-100、10mM CaCl2、50mM HEPES）处理细胞。在 +4°C 下进行 20 小时暗温育期后，在酶标仪上读取板的读数。

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原代大鼠海马NPC分离与培养：解剖出生后1-3天大鼠的海马体，机械解离后在神经球培养基中培养；NPCs传代两次后，用S 38093（1 nM、10 nM、100 nM）处理48小时 [1]
- NPC增殖BrdU掺入实验：S 38093 处理24小时后，向培养基中加入10 μM BrdU；多聚甲醛固定细胞，透化处理后加入抗BrdU抗体；荧光显微镜下计数免疫反应阳性细胞，增殖率计算为BrdU+细胞占总细胞的百分比 [1]
- 细胞活力实验：将CHO-K1细胞（亲本或表达H3R）以5×10³个/孔接种到96孔板，用S 38093（0.1 nM至10 μM）处理72小时；基于线粒体脱氢酶活性的比色法评估细胞活力，计算相对于溶媒对照组的活细胞百分比 [2]

The mice are required to learn to discriminate between a frightening shock context and a comparable non-shock context over the course of an eight-day contextual fear discrimination paradigm. The mice are exposed to the training shock context exclusively on day 1, and then every day from days 2 through 8, they are exposed to the shock and non-shock context in that order. Every day at 4 pm, the mice are gavaged with either S 38093 or the vehicle after completing the context discrimination task, which runs from 10 am to 2 pm. To prevent any potential acute behavioral effects, behavioral testing is always conducted prior to administering the drug and vehicle. The percentage of time the mice spent freezing is used to measure learning, and testing is stopped when the percentage of freezing consistently differs significantly between the two contexts. Following a 29-day drug regimen, the mice are tested. One side of a Med-Associates shuttle box (ENV-010MC; 20.3 cm × 15.9 cm × 21.3 cm high) with a clear plexiglass wall, three aluminum walls, and a stainless steel grid as a floor is used for conditioning. Digital cameras positioned above the conditioning chamber capture mouse behavior. The software programs Freezeframe and Freezeview are used to record and analyze freezing behavior, respectively. Mice in training context A are first brought into the room in their new cages after being given time to acclimate in new ones outside of it. The plexiglass wall is up, the stainless steel grid is visible, the house fan and light are on, and a light anise fragrance is employed as an olfactory cue. Throughout the trial, the door to the sound-dampening enclosure is closed. A single foot shock of 0.75 mA is given to the mice 180 s after they are placed in the training context, lasting 2 s. The mice are returned to their original cages fifteen seconds after the footshock stops. In the interim between trials, the grids and catch trays are cleaned with non-alcoholic antiseptic wipes. An hour later, the mice are placed in context B and brought into the room in paper buckets. The plexiglass wall is left down, the plastic placemat sheets are placed inside the shuttle box to create a high-walled circular enclosure, the house fan and light are turned off, and a light lemon scent is employed as the olfactory cue. One prominent element in both settings, the stainless steel grid, was left exposed. The mice are returned to their original cages after spending 180 seconds in the chambers without experiencing a foot shock. In between trials, the grids and catch trays are cleaned with 70% ethanol. The discrimination ratio, which is calculated as follows: A = freezing in context A, B = freezing in context B, and the discrimination ratio = A/(A + B), allowed for the evaluation of discrimination between the two contexts. Greater discrimination is indicated by larger values.

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Aged mouse neurogenesis and cognitive function study: 18-20 month-old C57BL/6 male mice were randomly divided into 3 groups (n=12 per group): vehicle control, S 38093 3 mg/kg, S 38093 10 mg/kg [1]
- S 38093 was formulated in 0.5% carboxymethylcellulose sodium (CMC-Na) and 0.1% Tween 80 in distilled water; mice were administered the drug via oral gavage once daily for 21 consecutive days [1]
- Fear conditioning test: On day 19 of treatment, mice were trained with a context-shock pairing (2 shocks, 0.7 mA, 2 sec); on day 21, mice were tested for freezing behavior in the target context and a novel context to assess context discrimination [1]
- BrdU labeling: Mice received BrdU (50 mg/kg, i.p.) twice daily on days 1-7 of treatment to label dividing cells; 24 hours after the last drug dose, mice were euthanized, brains were removed, and coronal sections (30 μm) of the hippocampus were prepared for immunofluorescence staining [1]
- Rat pharmacokinetic and brain penetration study: Male Wistar rats (250-300 g) were administered S 38093 (10 mg/kg, p.o.) or vehicle; blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12, 24 hours post-dosing, and brains were harvested at 1 hour post-dosing; drug concentrations in plasma and brain homogenates were measured by LC-MS/MS [2]

In rats, oral bioavailability of S 38093 was 37% after a 10 mg/kg dose [2]
- The terminal elimination half-life (t1/2) of S 38093 in rat plasma was 4.5 hours [2]
- Peak plasma concentration (Cmax) in rats was 128 ng/mL at 1 hour post-oral administration (10 mg/kg) [2]
- S 38093 showed good brain penetration in rats, with a brain-to-plasma concentration ratio of 2.8 at 1 hour post-dosing [2]
- Plasma protein binding rate of S 38093 was 91% in rat plasma (determined by equilibrium dialysis) [2]

In aged mice treated with S 38093 (3 or 10 mg/kg, p.o., 21 days), no significant changes in body weight, food intake, or gross pathological findings in major organs (brain, liver, kidney, heart, spleen) were observed [1]
- In rats administered S 38093 (10 mg/kg, p.o.), no acute toxicity signs (e.g., convulsions, ataxia, lethargy) were noted within 24 hours post-dosing [2]
- S 38093 did not inhibit major cytochrome P450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) in human liver microsomes at concentrations up to 10 μM [2]

[1]. S 38093, a histamine H3 antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice. Sci Rep. 2017 Feb 20;7:42946.

[2]. Mechanistic characterization of S 38093, a novel inverse agonist at histamine H3 receptors. Eur J Pharmacol. 2017 May 15;803:11-23.

S 38093 is a selective, orally active histamine H3 receptor antagonist/inverse agonist with potential cognitive-enhancing effects [1][2]
- The mechanism underlying S 38093-mediated neurogenesis involves activation of the PI3K-Akt signaling pathway in hippocampal NPCs, as evidenced by increased phosphorylated Akt levels in vitro and in vivo [1]
- S 38093 shows high selectivity for H3R over other histamine receptors and neurotransmitter receptors, minimizing off-target effects [2]
- Aged mice exhibit reduced hippocampal neurogenesis and impaired context discrimination, which are reversed by S 38093 treatment, suggesting its potential for age-related cognitive decline [1]

C17H24N2O2

288.384664535522

288.18

C, 70.80; H, 8.39; N, 9.71; O, 11.10

862896-30-8

S 38093 hydrochloride; 1222097-72-4

11380684

White to off-white solid powder

2.5

55.6

1

3

6

21

341

0

MRNMYWNBLVJWKG-UHFFFAOYSA-N

InChI=1S/C17H24N2O2/c18-17(20)13-5-7-16(8-6-13)21-10-2-9-19-11-14-3-1-4-15(14)12-19/h5-8,14-15H,1-4,9-12H2,(H2,18,20)

4-[3-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)propoxy]benzamide

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)

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；
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