BNC375
目录号 : GC35538
BNC375 是一种口服有效的选择性 α7nAChRs I 型正向变构调节剂，EC50 为 1.9 μM。
Cas No.:1557240-80-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
BNC375 is a potent, selective, and orally available type I positive allosteric modulator of α7 nAChRs with an EC50 of 1.9 μM[1].
[1]. Andrew J. Harvey, et al. Discovery of BNC375, a Potent, Selective, and Orally Available Type I Positive Allosteric Modulator of α7 nAChRs. Cite This:ACS Med. Chem. Lett.2019105754-760.
| Cas No. | 1557240-80-8 | SDF | |
| Canonical SMILES | ClC1=CC=C(OC)C(NC[C@H]2C(C)(C)[C@@H]2C3=CC=C(S(N)(=O)=O)C=C3)=C1 | ||
| 分子式 | C19H23ClN2O3S | 分子量 | 394.92 |
| 溶解度 | Soluble in DMSO | 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 | 2.5322 mL | 12.6608 mL | 25.3216 mL |
| 5 mM | 0.5064 mL | 2.5322 mL | 5.0643 mL |
| 10 mM | 0.2532 mL | 1.2661 mL | 2.5322 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
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，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Pharmacological Characterization of the Novel and Selective α 7 Nicotinic Acetylcholine Receptor-Positive Allosteric Modulator BNC375
J Pharmacol Exp Ther 2020 May;373(2):311-324.PMID:32094294DOI:10.1124/jpet.119.263483.
Treatments for cognitive deficits associated with central nervous system (CNS) disorders such as Alzheimer disease and schizophrenia remain significant unmet medical needs that incur substantial pressure on the health care system. The α7 nicotinic acetylcholine receptor (nAChR) has garnered substantial attention as a target for cognitive deficits based on receptor localization, robust preclinical effects, genetics implicating its involvement in cognitive disorders, and encouraging, albeit mixed, clinical data with α7 nAChR orthosteric agonists. Importantly, previous orthosteric agonists at this receptor suffered from off-target activity, receptor desensitization, and an inverted U-shaped dose-effect curve in preclinical assays that limit their clinical utility. To overcome the challenges with orthosteric agonists, we have identified a novel selective α7 positive allosteric modulator (PAM), BNC375. This compound is selective over related receptors and potentiates acetylcholine-evoked α7 currents with only marginal effect on the receptor desensitization kinetics. In addition, BNC375 enhances long-term potentiation of electrically evoked synaptic responses in rat hippocampal slices and in vivo. Systemic administration of BNC375 reverses scopolamine-induced cognitive deficits in rat novel object recognition and rhesus monkey object retrieval detour (ORD) task over a wide range of exposures, showing no evidence of an inverted U-shaped dose-effect curve. The compound also improves performance in the ORD task in aged African green monkeys. Moreover, ex vivo 13C-NMR analysis indicates that BNC375 treatment can enhance neurotransmitter release in rat medial prefrontal cortex. These findings suggest that α7 nAChR PAMs have multiple advantages over orthosteric α7 nAChR agonists for the treatment of cognitive dysfunction associated with CNS diseases. SIGNIFICANCE STATEMENT: BNC375 is a novel and selective α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) that potentiates acetylcholine-evoked α7 currents in in vitro assays with little to no effect on the desensitization kinetics. In vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that α7 nAChR PAMs have therapeutic potential in central nervous system diseases with cognitive impairments.
Discovery of BNC375, a Potent, Selective, and Orally Available Type I Positive Allosteric Modulator of α7 nAChRs
ACS Med Chem Lett 2019 Mar 25;10(5):754-760.PMID:31097995DOI:10.1021/acsmedchemlett.9b00001.
Positive allosteric modulators (PAMs) of α7 nAChRs can have different properties with respect to their effects on channel kinetics. Type I PAMs amplify peak channel response to acetylcholine but do not appear to influence channel desensitization kinetics, whereas Type II PAMs both increase channel response and delay receptor desensitization. Both Type I and Type II PAMs are reported in literature, but there are limited reports describing their structure-kinetic profile relationships. Here, we report a novel class of compounds with either Type I or Type II behavior that can be tuned by the relative stereochemistry around the central cyclopropyl ring: for example, (R,R)-13 (BNC375) and its analogues with RR stereochemistry around the central cyclopropyl ring are Type I PAMs, whereas compounds in the same series with SS stereochemistry (e.g., (S,S)-13) are Type II PAMs as measured using patch-clamp electrophysiology. Further fine control over the kinetics has been achieved by changing the substitutions on the aniline ring: generally the substitution of aniline with strong electron withdrawing groups reduces the Type II character of these compounds. Our structure-activity optimization efforts have led to the discovery of BNC375, a small molecule with good CNS-drug like properties and clinical candidate potential.
A Novel Biomarker of Neuronal Glutamate Metabolism in Nonhuman Primates Using Localized 1H-Magnetic Resonance Spectroscopy: Development and Effects of BNC375, an α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulator
Biol Psychiatry Cogn Neurosci Neuroimaging 2022 Jun;7(6):598-606.PMID:PMC8005500DOI:10.1016/j.bpsc.2020.09.014.
Background: The development of treatments for cognitive deficits associated with central nervous system disorders is currently a significant medical need. Despite the great need for such therapeutics, a significant challenge in the drug development process is the paucity of robust biomarkers to assess target modulation and guide clinical decisions. We developed a novel, translatable biomarker of neuronal glutamate metabolism, the 13C-glutamate+glutamine (Glx) H3:H4 labeling ratio, in nonhuman primates using localized 1H-magnetic resonance spectroscopy combined with 13C-glucose infusions. Methods: We began with numerical simulations in an established model of brain glutamate metabolism, showing that the 13C-Glx H3:H4 ratio should be a sensitive biomarker of neuronal tricarboxylic acid cycle activity, a key measure of overall neuronal metabolism. We showed that this biomarker can be measured reliably using a standard 1H-magnetic resonance spectroscopy method (point-resolved spectroscopy sequence/echo time = 20 ms), obviating the need for specialized hardware and pulse sequences typically used with 13C-magnetic resonance spectroscopy, thus improving overall clinical translatability. Finally, we used this biomarker in 8 male rhesus macaques before and after administration of the compound BNC375, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor that enhances glutamate signaling ex vivo and elicits procognitive effects in preclinical species. Results: The 13C-Glx H3:H4 ratios in the monkeys showed that BNC375 increases neuronal metabolism in nonhuman primates in vivo, detectable on an individual basis. Conclusions: This study demonstrates that the ratio of 13C-Glx H3:H4 labeling is a biomarker that may provide an objective readout of compounds affecting glutamatergic neurotransmission and could improve decision making for the development of therapeutic agents.