TPA-023B
目录号 : GC67996TPA-023B 是一种高亲和力的口服活性的 GABAA 受体 α2/α3 亚型 (Ki 为 0.73 nM/2 nM) 部分激动剂和 α1 亚型 (Ki 为 1.8 nM) 拮抗剂。TPA-023B 具有非镇静抗焦虑特性。
Cas No.:425377-76-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
TPA-023B is a high-affinity and orally active GABAA receptor α2/α3 subtype (Kis of 0.73 nM/2 nM) partial agonist and a α1 subtype (Ki of 1.8 nM) antagonist. TPA-023B has non-sedating anxiolytic-like properties[1].
TPA-023B also has high affinity for α5 subtype (Ki of 1.1 nM) of human recombinant GABAA receptor, but over 1500-fold lower for the α4- and α6 containing subtypes (Ki > 1000 nM). TPA-023B also has a comparable affinity for native rat GABAA receptors in different regions of the CNS (Ki of 0.32-0.99 nM in cerebellum, spinal cord and frontal cortex)[1].
TPA-023B antagonizes the ability of chlordiazepoxide to potentiate the GABA EC20-induced current in cells expressing the α1 subtype. More specifically, 3 μM chlordiazepoxide potentiates the GABA EC20 current by 105% and this effect could be reduced to 8% in the presence of 100 nM TPA-023B[1].
TPA-023B gives dose- and time-dependent occupancy of rat brain GABAA receptors as measured using an in vivo [3H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL[1].
TPA-023B is anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet has no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%[1].
[1]. Atack JR, et al. Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist. J Psychopharmacol. 2011 Mar;25(3):329-44.
| Cas No. | 425377-76-0 | SDF | Download SDF |
| 分子式 | C21H15F2N5O | 分子量 | 391.37 |
| 溶解度 | 储存条件 | Store at -20°C | |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.5551 mL | 12.7756 mL | 25.5513 mL |
| 5 mM | 0.511 mL | 2.5551 mL | 5.1103 mL |
| 10 mM | 0.2555 mL | 1.2776 mL | 2.5551 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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GABAA receptor alpha2/alpha3 subtype-selective modulators as potential nonsedating anxiolytics
Curr Top Behav Neurosci 2010;2:331-60.PMID:21309116DOI:10.1007/7854_2009_30.
Nonselective benzodiazepines exert their pharmacological effects via GABAA receptors containing either an alpha1, alpha2, alpha3, or alpha5 subunit. The use of subtype-selective tool compounds along with transgenic mice has formed the conceptual framework for defining the requirements of subtype-selective compounds with potentially novel pharmacological profiles. More specifically, compounds which allosterically modulate the alpha2 and/or alpha3 subtypes but are devoid of, or have much reduced, effects at the alpha1 subtype are hypothesized to be anxioselective (i.e., anxiolytic but devoid of sedation). Accordingly, three compounds, MRK-409, TPA023 and TPA023B, which selectively potentiated the effects of GABA at the alpha2 and alpha3 compared to alpha1 subtypes were progressed into man. All three compounds behaved as nonsedating anxiolytics in preclinical (rodent and primate) species but, surprisingly, MRK-409 produced sedation in man at relatively low levels of occupancy (< 10%). This sedation liability of MRK-409 in man was attributed to its weak partial agonist efficacy at the alpha1 subtype since both TPA023 and TPA023B lacked any alpha1 efficacy and did not produce overt sedation even at relatively high levels of occupancy (> 50%). The anxiolytic efficacy of TPA023 was evaluated in Generalized Anxiety Disorder and although these clinical trials were terminated early due to preclinical toxicity issues, the combined data from these incomplete studies demonstrated an anxiolytic-like effect of TPA023. This compound also showed a trend to increase cognitive performance in a small group of schizophrenic subjects and is currently under further evaluation of its cognition-enhancing effects in schizophrenia as part of the TURNS initiative. In contrast, the fate of the back-up clinical candidate TPA023B has not been publicly disclosed. At the very least, these data indicate that the pharmacological profile of compounds that differentially modulate specific populations of GABAA receptors is distinct from classical benzodiazepines and should encourage further preclinical and clinical investigation of such compounds, with the caveat that, as exemplified by MRK-409, the preclinical profile might not necessarily translate into man.