AMPA receptor; PAM/positive allosteric modulator

CX 516是一种苄基哌啶AMPAkine，一种AMPA（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸）调节剂，当谷氨酸与AMPA受体通道复合物发生变构结合时，可以增强谷氨酸的功能。CX 516通过更长的开放时间、较慢的兴奋性突触后电位（EPSP）衰减和海马长期增强（LTP）的改善来减缓受体失活。

皮下注射CX516（10 和 20 mg/kg）可显着减少产后早期或亚慢性苯环己哌啶治疗引起的某些超维度缺陷[1]。

---

结果：舍托吲哚显著减轻了亚慢性或出生后早期PCP治疗产生的特异性外维度缺陷，CX516呈剂量依赖性。
结论：这里的研究结果进一步证实了PCP治疗是与精神分裂症相关的执行功能缺陷的模型，并提供了证据表明，在ID-ED注意力转移任务中进行评估时，直接的谷氨酸能干预可以改善这些缺陷。
关于急性药理学挑战的影响，舍托吲哚（1.25 mg/kg，口服）能有效逆转亚慢性五氯苯酚引起的ED转换性能缺陷（p < 0.001) 产后早期PCP（p < 0.001),两者均与急性盐水挑战相比。同样，两剂CX516（10和20 mg/kg，皮下注射）具有高度显著性（p ≤ 0.001) 改善由两种治疗方案引起的ED转移缺陷。有趣的是，皮下注射5和40 mg/kg的CX516在逆转亚慢性五氯苯酚治疗方案引起的ED损伤方面无效。与之形成鲜明对比的是，5 mg/kg的CX516剂量能够逆转出生后早期五氯苯酚引起的ED缺陷（p < 0.05). 在有效逆转ED移位缺陷的治疗方法中（两种模型中的舍曲吲哚和CX516、5（仅产后早期PCP）、10和20mg/kg），这两组在ED辨别评分方面均与赋形剂治疗的对照组没有显著差异[1]。

---

在临床环境中，一项初步研究表明，当作为氯氮平的补充治疗时，CX516具有积极的临床效果（Goff等人，2001）。不幸的是，尽管具有良好的统计能力和较低的损耗，但这些发现在最近的一项随访研究中无法重复（Goff等人，2008）。众所周知，CX516是一种低效药物（综述见Arai和Kessler 2007；Black 2005）；因此，次优暴露可能是临床研究中缺乏效果的原因。尽管很少有临床研究报告血浆浓度水平，但对于平均体重的人来说，900毫克的常用临床剂量可转化为约13毫克/千克（口服），相当于约8µM的血浆浓度（Lynch等人，1997；Ingvar等人，1997）。尽管人类的清除率较低，但这种相对较低的血浆水平可能解释了阴性临床结果。这在一定程度上得到了当前研究数据的支持，其中5 mg/kg CX516的剂量在亚慢性五氯苯酚治疗方案中没有改善大鼠ID-ED测试性能，在出生后早期五氯苯酚治疗治疗方案中仅显示出最小的显著性。尽管在出生后早期PCP治疗方案中，CX516逆转注意集转移缺陷没有发现无效应限制，但似乎在精神分裂症的两种动物模型中都存在“U”型剂量-反应关系。较低剂量（5mg/kg）的效果缺失或减弱可以简单地用较低的血浆浓度来解释，从而降低了大脑暴露，亚慢性五氯苯酚治疗的动物就是这种情况。然而，对于出生后早期接受五氯苯酚治疗的动物，5-mg/kg剂量的影响可能表明在该动物模型中对CX516暴露的敏感性更高。

在另一项临床研究中，CX516作为单一药物给药，但在改善精神分裂症患者的精神病和认知措施方面无效；然而，这项初步研究的动力不足，患者退出，尤其是在较高剂量的CX516下（Marenco等人，2002）。在本研究中，在两种动物疾病模型中都观察到40 mg/kg剂量下CX516逆转效应的“清除”。在另一项动物研究中观察到较高剂量下的行为改变，其中观察到探索行为受到抑制（Granger等人，1993）。在目前的研究中，CX516在5-40mg/kg的剂量下没有观察到明显的不良反应；然而，在一项测试80mg/kg剂量的试点研究中，我们观察到大鼠对挖掘食物奖励失去了兴趣。相反，他们表现出明显的舔舐行为，在测试箱中舔舐硅胶连接。尽管是推测性的，但我们认为这可能是由于CX516对谷氨酸能系统的刺激引起的兴奋毒性作用。

文献中有许多研究描述了脑切片和动物模型中的CX516功能（综述见Arai和Kessler 2007；Black 2005）。一般来说，当在海马切片中进行研究时，CX516的作用来自增强AMPA受体传递和促进长期增强（LTP）形成的能力（Granger等人，1993；Staubli等人，1994；Arai等人，94）。由于体内研究的结果也表明CX516可以促进LTP，因此随后在许多记忆动物模型中对其积极作用进行了研究。CX516管理已被证明可以促进长期参考记忆，以及短期和工作记忆（有关综述，请参阅Black 2005）。有趣的是，在随后两项研究AMPA功能的研究中，首次表明CX516在海马切片中没有增强LTP（只是降低了刺激阈值），而在PFC切片中却增强了LTP（Black等人，2000）。此外，CX516已被证明在体外和体内都能增强PFC中的AMPA反应（Baumbarger等人，2001）。尽管这些数据集之间的差异尚不清楚，但从理论上讲，后一种数据集与目前的数据相结合，将使CX516成为治疗精神分裂症中PFC介导的执行功能缺陷的理想选择[1]。

Animal/Disease Models: Male Lister Hooded rat (56-63 days after birth) [1]
Doses: 5, 10, 20 and 40 mg/kg
Route of Administration: subcutaneous injection
Experimental Results: Two doses (10 and 20 mg/kg) The improvement in extradimensional transformation defects caused by either treatment regimen is very significant. Two doses (5 and 40 mg/kg) were ineffective in reversing extradimensional damage induced by subchronic postpartum phencyclidine regimen.

---

For comparative evaluation of the effect on deficits in executive functioning, sertindole was dosed 120 min prior to presentation of the first discrimination problem (1.25 mg/kg, perorally (p.o.)), and this dose was adapted from Goetghebeur and Dias (2009) and Rodefer et al. (2008). Based on exposure data (see Table 1), it was determined to dose CX516 (5, 10, 20, and 40 mg/kg, s.c.) at two time points, first 30 min prior to presentation of the first discrimination and second approximately 60 min later (before starting the intradimensional shift 2 reversal discrimination), meaning that all animals were dosed at the same stage of the ID–ED task. Control animals (acute vehicle injections) were counterbalanced for s.c. and p.o. administrations, and the different vehicles were applied.[1]

---

CX516 was dissolved in isotonic water (D-glucose) and pH adjusted to 7 using methansulfonic acid.
Exposure: Exposure data of CX516 were collected in two separate experiments. Firstly, the pharmacokinetic profile of CX516 was assessed for a dose of 40 mg/kg (s.c), with collections at 30, 60, and 90 min (n = 4), in both the sub-chronic and early postnatal animal disease models. Secondly, in order to investigate the relationship between CX516 plasma and brain concentrations and the effect on reversal of the PCP-induced ED shift performance deficit (pharmacodynamics), CX516 was dosed (5, 10, 20, or 40 mg/kg) twice, first at 30 min prior to the presentation of the first discrimination and again approximately 60 min later. Samples were collected at 90 min (n = 4) [1].

[1]. Reversal of cognitive deficits by an ampakine (CX516) and sertindole in two animal models of schizophrenia--sub-chronic and early postnatal PCP treatment in attentional set-shifting. Psychopharmacology (Berl). 2009 Nov;206(4):631-40.

CX-516 is a N-acylpiperidine.

---

Drug Indication
Investigated for use/treatment in alzheimer's disease, memory loss, autism, neurologic disorders, dementia, schizophrenia and schizoaffective disorders, attention deficit/hyperactivity disorder (ADHD), and sleep disorders.

---

Mechanism of Action
CX 516 is a benzylpiperidine AMPAkine, an AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) modulator, that enhances the function of glutamate when it binds allosterically to the AMPA receptor channel complex. CX516 slows receptor deactivation with a longer open time, slower excitatory postsynaptic potential (EPSP) decay and improvement of hippocampal long term potentiation (LTP).

---

Rationale: Therapies treating cognitive impairments in schizophrenia especially deficits in executive functioning are not available at present. Objective: The current study evaluated the effect of ampakineCX516 in reversing deficits in executive functioning as represented in two animal models of schizophrenia and assessed by a rodent analog of the intradimensional-extradimensional (ID-ED) attentional set-shifting task. The second generation antipsychotic, sertindole, provided further validation of the schizophrenia-like disease models. Methods: Animals were subjected to (a) sub-chronic or (b) early postnatal phencyclidine (PCP) treatment regimes: (a) Administration of either saline or PCP (5 mg/kg, intraperitonally b.i.d. for 7 days) followed by a 7-day washout period and testing on day 8. (b) On postnatal days (PNDs) 7, 9, and 11, rats were subjected to administration of either saline or PCP (20 mg/kg, subcutaneously (s.c.)) and tested on PNDs 56-95, after reaching adulthood. The single test session required rats to dig for food rewards in a series of discriminations following acute administration of either vehicle, or CX516 (5-40 mg/kg, s.c.), or sertindole (1.25 mg/kg, perorally). [1]

---

In summary, schizophrenia-related cognitive impairments are poorly treated by existing therapies, possibly due to an exclusive focus on dopamine D2 receptor antagonism, as being the main predictor of drug efficiency (Weinberger 2007). The current study represents a different approach building on the glutamate hypothesis of schizophrenia, suggesting disturbances in the glutamate homeostasis as an underlying cause of the executive functioning deficits seen in schizophrenia (Owen et al. 1991). The two animal models of schizophrenia (i.e., sub-chronic and early postnatal PCP models) tested here represents different ways to model the schizophrenia disease pattern. And although similar in their detection of effects in the ID–ED task when treated with CX516 and sertindole, there are important differences, like the time required to prepare animals and consistency of the induced deficit. Indeed, the early postnatal model takes longer to prepare, but then offers a larger window for applying chronic antipsychotic drug treatment to mimic the clinical situation more closely. This study emphasizes the important role of glutamate homeostasis in the brain and increases our insight into possible novel treatment regimens for cognitive disturbances affecting schizophrenia patients. Interestingly, attempts to reverse the PCP-induced deficits in attentional set-shifting by the use of the ampakine CX516 and the second generation antipsychotic sertindole were similar in these theoretically different animal models of schizophrenia. These data add further to support the potential of both approaches in relieving the cognitive deficits associated with schizophrenia, thereby improving the translational aspect of the ID–ED test paradigm. [1]

C14H15N3O

241.294

241.121

C, 69.69; H, 6.27; N, 17.41; O, 6.63

154235-83-3

CX516-d10;1286653-21-1

148184

White to light yellow solid powder

1.2±0.1 g/cm3

433.1±25.0 °C at 760 mmHg

88-90ºC

215.8±23.2 °C

0.0±1.0 mmHg at 25°C

1.640

0.57

46.09

0

3

1

18

301

0

C1CCN(CC1)C(=O)C2=CC3=NC=CN=C3C=C2

ANDGGVOPIJEHOF-UHFFFAOYSA-N

InChI=1S/C14H15N3O/c18-14(17-8-2-1-3-9-17)11-4-5-12-13(10-11)16-7-6-15-12/h4-7,10H,1-3,8-9H2

piperidin-1-yl(quinoxalin-6-yl)methanone

BDP 12; BDP-12; CX-516; BDP12; Ampalex; 154235-83-3; BDP 12; 1-(quinoxalin-6-ylcarbonyl)piperidine; 1-(6-Quinoxalinylcarbonyl)piperidine; SPD-420; CX 516; CX516; SPD420; brand name: Ampalex;

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)

H2O : ~100 mg/mL (~414.44 mM)
DMSO : ≥ 41 mg/mL (~169.92 mM)

配方 1 中的溶解度: ≥ 2.75 mg/mL (11.40 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 27.5 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

配方 2 中的溶解度: ≥ 2.75 mg/mL (11.40 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 27.5mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，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。

---

View More

配方 3 中的溶解度: ≥ 2.75 mg/mL (11.40 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 27.5 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

---

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。