Linopirdine
(Synonyms: 利诺吡啶,DuP 996) 目录号 : GC44075
A neurotransmitter release enhancer
Cas No.:105431-72-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Linopirdine is an enhancer of the stimulus-evoked but not basal release of several neurotransmitters, including acetylcholine, dopamine, serotonin, and glutamate. It increases acetylcholine release in rat hippocampal CA1 neurons by blocking voltage-gated, calcium-activated and leak (M-type; Kv7.2/7.3; KCNQ2/3) K+ current with an IC50 value of 2.4 µM. Inhibition of M-channels is reported to result in the depolarization of CA3 pyramidal neurons and activated presynaptic voltage-gated P/Q- and N-type calcium channels, which leads to Ca2+ influx and increased neurotransmitter release. Linopirdine has been shown to produce a number of effects including EEG patterns of enhanced vigilance, induction of c-fos expression in cerebral cortex, reduction of the increase of cerebral glucose utilization induced by hypoxia, and improved performance in animal models of learning and memory. Linopirdine has also been identified as an agonist of transient receptor potential vanilloid type 1 (EC50 = 115 µM in HEK293 cells voltage clamped at -60 mV).
| Cas No. | 105431-72-9 | SDF | |
| 别名 | 利诺吡啶,DuP 996 | ||
| Canonical SMILES | O=C1C(CC2=CC=NC=C2)(CC3=CC=NC=C3)C4=CC=CC=C4N1C5=CC=CC=C5 | ||
| 分子式 | C26H21N3O | 分子量 | 391.5 |
| 溶解度 | DMF: 30 mg/mL,DMSO: 25 mg/mL,Ethanol: 30 mg/mL,Ethanol:PBS (pH 7.2) (1:30): 0.03 mg/mL | 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 | 2.5543 mL | 12.7714 mL | 25.5428 mL |
| 5 mM | 0.5109 mL | 2.5543 mL | 5.1086 mL |
| 10 mM | 0.2554 mL | 1.2771 mL | 2.5543 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 |
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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，
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。
[3H]Linopirdine binding to rat brain membranes is not relevant for M-channel interaction
Eur J Pharmacol 2005 Jul 25;518(1):10-7.PMID:16018996DOI:10.1016/j.ejphar.2005.06.005.
Linopirdine was developed as a cognitive enhancing molecule and demonstrated to specifically block the potassium current generated by the brain specific KCNQ2-KCNQ3 proteins (M-channel). In this study we investigated the relevance of [(3)H]Linopirdine binding in rat brain extracts to the interaction with the M-channel proteins. Our results confirm the presence of a high affinity site for [(3)H]Linopirdine in rat brain tissues (KD = 10 nM) but we also identified a high affinity binding site for [(3)H]Linopirdine in rat liver tissues (KD = 9 nM). Competition experiments showed that [(3)H]Linopirdine is displaced by unlabelled Linopirdine with comparable affinities from its binding sites on rat brain and rat liver membranes. [(3)H]Linopirdine was completely displaced by a set of cytochrome P450 (CYP450) ligands suggesting that [(3)H]Linopirdine binding to rat brain and liver membranes is linked to CYP450 interaction. The testing of CYP450 ligands on the M-channel activity, using a Rb(+) efflux assay on cells expressing the KCNQ2-KCNQ3 proteins, demonstrated that [(3)H]Linopirdine binding results cannot be correlated to M-channel inhibition. The results obtained in this study demonstrate that [(3)H]Linopirdine binding to rat brain and rat liver membranes is representative for CYP450 interaction and not relevant for the binding to the M-channel proteins.
Linopirdine-supplemented resuscitation fluids reduce mortality in a model of ischemia-reperfusion injury induced acute respiratory distress syndrome
Physiol Res 2021 Aug 31;70(4):649-953.PMID:34062081DOI:10.33549/physiolres.934679.
Previously, we demonstrated that supplementation of resuscitation fluids with the Kv7 voltage-activated potassium channel inhibitor Linopirdine reduces fluid resuscitation requirements and stabilizes hemodynamics in various rat models of hemorrhagic shock. To further evaluate the therapeutic potential of Linopirdine, we tested the effects of linopirdine-supplemented resuscitation fluids in a rat model of ischemia-reperfusion injury-induced acute respiratory distress syndrome (ARDS). Ventilated rats underwent unilateral lung ischemia from t=0-75 min, followed by lung reperfusion and fluid resuscitation to a mean arterial blood pressure of 60 mmHg with normal saline (NS, n=9) or NS supplemented with 50 µg/ml linopridine (NS-L), n=7) until t=360 min. As compared with NS, fluid resuscitation with NS-L stabilized blood pressure and reduced fluid requirements by 40% (p<0.05 vs. NS at t=240-360 min). While NS-L did not affect ARDS development, it reduced mortality from 66% with NS to 14% with NS-L (p=0.03, hazard ratio 0.14; 95% confidence interval of the hazard ratio: 0.03-0.65). Median survival time was 240 min with NS and >360 min with NS-L. As compared with NS treated animals that survived the observation period (n=3), however, plasma lactate and creatinine concentrations at t=360 min were higher with NS-L (n=6; p<0.05). Our findings extend therapeutic potential of NS-L from hypovolemic/hemorrhagic shock to hemodynamic instability under normovolemic conditions during organ ischemia-reperfusion injury. Possible adverse effects of NS-L, such as impairment of renal function and/or organ hypoperfusion, require further evaluation in long-term pre-clinical models.
Linopirdine (DuP 996) improves performance in several tests of learning and memory by modulation of cholinergic neurotransmission
Pharmacol Biochem Behav 1994 Dec;49(4):1075-82.PMID:7886078DOI:10.1016/0091-3057(94)90267-4.
The actions of Linopirdine (DuP 996; 3,3-bis[4-pyrindinylmethyl]-1-phenylindolin-2-one) were evaluated in rats and mice in several cognitive behavioral tests, and for its effects on hippocampal acetylcholine (ACh) overflow in rats. Using mice treated with the muscarinic receptor antagonist, scopolamine, we studied the effects of Linopirdine on retention of a passive avoidance task. Linopirdine (0.1 and 1 mg/kg) ameliorated the scopolamine-induced deficit, but at doses ranging from 0.01-1 mg/kg, it did not affect passive avoidance retention in normal (untreated) mice. In a scopolamine-induced hyperactivity test, Linopirdine (1 mg/kg) decreased the motoric stimulation associated with the cholinergic hypofunction, without affecting locomotor activity on its own. Using rats, we studied the effects of Linopirdine on performance in the Morris water maze spatial memory task. Young rats treated with atropine (30 mg/kg), a muscarinic receptor antagonist, took significantly longer to locate the submerged platform across 12 trials. Linopirdine (0.01 and 0.1, but not 1 mg/kg) ameliorated the atropine deficit. In addition, Linopirdine (0.1 mg/kg) ameliorated the deficit in cognition-impaired aged rats (23-24 mo), but did not affect unimpaired aged rats. In terms of neurochemical action, Linopirdine (1, 10, and 100 microM) produced a concentration-dependent increase in K(+)-evoked ACh overflow from superfused rat hippocampal slices. Also, Linopirdine (10 microM) similarly increased ACh release in young control rats and cognition-impaired and nonimpaired aged rats. Our results confirm and extend findings from other studies that demonstrate the cognition-enhancing action of Linopirdine in rodent models.(ABSTRACT TRUNCATED AT 250 WORDS)
The M-channel blocker Linopirdine is an agonist of the capsaicin receptor TRPV1
J Pharmacol Sci 2010;114(3):332-40.PMID:21099148DOI:10.1254/jphs.10172fp.
Linopirdine is a well known blocker of voltage-gated potassium channels from the Kv7 (or KCNQ) family that generate the so called M current in mammalian neurons. Kv7 subunits are also expressed in pain-sensing neurons in dorsal root ganglia, in which they modulate neuronal excitability. In this study we demonstrate that Linopirdine acts as an agonist of TRPV1 (transient receptor potential vanilloid type 1), another ion channel expressed in nociceptors and involved in pain signaling. Linopirdine induces increases in intracellular calcium concentration in human embryonic kidney 293 (HEK293) cells expressing TRPV1, but not TRPA1 and TRPM8 or in wild-type HEK293 cells. Linopirdine also activates an inward current in TRPV1-expressing HEK293 cells that is almost completely blocked by the selective TRPV1 antagonist capsazepine. At low concentrations Linopirdine sensitizes both recombinant and native TRPV1 channels to heat, in a manner that is not prevented by the Kv7-channel opener flupirtine. Taken together, these results indicate that Linopirdine exerts an excitatory action on mammalian nociceptors not only through inhibition of the M current but also through activation of the capsaicin receptor TRPV1.
A randomized, controlled trial of Linopirdine in the treatment of Alzheimer's disease
Can J Neurol Sci 1997 May;24(2):140-5.PMID:9164692DOI:10.1017/s031716710002148x.
Objectives: We tested the efficacy and safety of Linopirdine, a novel phenylindolinone, in the treatment of Alzheimer's disease. Methods: A multicentre, randomized, double-blind, parallel group, placebo-controlled trial of Linopirdine (30 mg three times per day or placebo). Patients (n = 382, 55% male, 98% Caucasian, age range 51-95 years) with mild or moderate Alzheimer's disease, of whom 375 received at least one treatment dose were analysed. There were no important differences between the groups at baseline. Results: No difference was seen in Clinical Global Impression scores between patients receiving placebo and those receiving Linopirdine (n = 189). Small differences in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores were seen throughout the study favouring Linopirdine; at 6 months the ADAS-Cog scores were 20.2 (Linopirdine) and 22.1 (placebo) p = 0.01. Conclusions: This trial did not detect clinically meaningful differences in patients receiving Linopirdine for 6 months, despite evidence of a small degree of improved cognitive function. Further studies may benefit from more sensitive tests of treatment effects in Alzheimer's disease.