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| Targets |
Linopirdine targets voltage-gated potassium channels of the Kv7 (KCNQ) family. It is a potent blocker of these channels, particularly the M-type K+ current (IM) which is formed by KCNQ2 and KCNQ3 subunits. By blocking these channels, linopirdine enhances neuronal excitability and promotes neurotransmitter release, especially acetylcholine. It also acts as an agonist of the capsaicin receptor TRPV1.
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| ln Vitro |
Linopirdine (DuP 996) suppresses IC with an IC50 of 16.3 μM, as assessed by moderate ultra-instantaneous tail current, or ImAHP. At 100 μM, linapirdine barely suppresses the slow levels of K+ leakage current (IL), transient outward current (IA), delay regulator (IK), and IAHP by 28, 37, 36, and 52%, in that order. Linopirdine (IC50>300 μM) essentially has no effect on the Na+/K+ mixed inward corrective current IQ[1]. An agonist of TRPV1 (transient transient potential vanilloid type 1) is linopirdine [3].
Linopirdine is a potent blocker of Kv7 channels with IC50 values of 4-7 μM for KCNQ2+3/M-currents and 8.9 μM for KCNQ1 homomeric channels. By inhibiting M-type K+ current, linopirdine increases acetylcholine release in rat hippocampal CA1 neurons. This mechanism is thought to underlie its potential as a cognition enhancer. |
| ln Vivo |
Up to 15% of MAP is temporarily increased (10–15 minutes) by linopridine (DuP 996; IV; 0.1-6 mg/kg; escalating dose) and dose stress [2].
Linopirdine is active in vivo and has been studied for its potential therapeutic applications. As a putative cognition enhancer, it has been evaluated in animal models of cognitive impairment. It has also been studied for its potential in treating various neurological and psychiatric disorders. However, specific in vivo efficacy data is not detailed in the available literature. |
| Enzyme Assay |
The in vitro activity of Linopirdine is assessed using electrophysiological techniques. In these assays, cells expressing Kv7 channels (such as KCNQ2+3 or KCNQ1) are subjected to patch-clamp recording. The compound is applied at various concentrations, and its effect on the M-type potassium current is measured. IC50 values are calculated from the concentration-response curves.
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| Cell Assay |
Cell-based assays are used to evaluate Linopirdine's activity. Cells expressing Kv7 channels are loaded with a voltage-sensitive dye or subjected to electrophysiological recording. The compound's ability to block potassium currents is measured. Additionally, its effect on neurotransmitter release can be assessed in neuronal cultures by measuring the release of acetylcholine or other neurotransmitters.
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| Animal Protocol |
Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat (300-350) g)[2]
Doses: 0.1, 0.5, 1, 3, 6 mg/kg Route of Administration: 5 intravenous (iv) (iv)bolus injections, dose escalation Experimental Results: Transient and dose Dependently increases MAP by up to 15%. Linopirdine has been evaluated in animal models of cognitive impairment. In these studies, the compound is typically administered orally or intraperitoneally to rodents, and its effects on learning and memory are assessed using behavioral tests such as the Morris water maze or passive avoidance test. Its effects on neurotransmitter release in the brain can also be measured using microdialysis. |
| ADME/Pharmacokinetics |
Linopirdine has a molecular weight of 391.47 and a molecular formula of C26H21N3O. The IUPAC name is 1-phenyl-3,3-bis(pyridin-4-ylmethyl)indol-2-one. It is soluble in DMSO (10 mM). Powder should be stored at -20°C for up to 12 months, and in solvent at -80°C for 6 months or -20°C for 6 months. Purity is typically >98%.
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| Toxicity/Toxicokinetics |
Linopirdine is a research compound and its full toxicological profile is not detailed in the available literature. As a Kv7 channel blocker and putative cognition enhancer, its safety profile has been evaluated in preclinical studies. It has been used in animal studies at various doses without significant adverse effects reported. Standard safety precautions should be followed when handling the compound.
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| References |
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| Additional Infomation |
Linopirdine is a member of the indole class of compounds.
Linopirdine (CAS#: 105431-72-9) is a potent Kv7 (KCNQ) voltage-gated potassium channel blocker, also known as DUP-996. It blocks KCNQ2+3/M-currents (IC50 = 4-7 μM) and KCNQ1 channels (IC50 = 8.9 μM). Linopirdine increases acetylcholine release in rat hippocampal CA1 neurons and is active in vivo. It has been extensively studied as a putative cognition enhancer. |
| Molecular Formula |
C26H21N3O
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|---|---|
| Molecular Weight |
391.47
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| Exact Mass |
391.168
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| CAS # |
105431-72-9
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| Related CAS # |
Linopirdine dihydrochloride;113168-57-3
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| PubChem CID |
3932
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.255 g/cm3
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| Boiling Point |
655.9ºC at 760 mmHg
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| Flash Point |
350.5ºC
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| Vapour Pressure |
4.45E-17mmHg at 25°C
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| Index of Refraction |
1.669
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| LogP |
4.943
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
30
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| Complexity |
555
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
YEJCDKJIEMIWRQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H21N3O/c30-25-26(18-20-10-14-27-15-11-20,19-21-12-16-28-17-13-21)23-8-4-5-9-24(23)29(25)22-6-2-1-3-7-22/h1-17H,18-19H2
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| Chemical Name |
1-phenyl-3,3-bis(pyridin-4-ylmethyl)indol-2-one
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| Synonyms |
DuP-996; DuP 996; Linopirdine
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~319.32 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.31 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.31 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.31 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5545 mL | 12.7724 mL | 25.5447 mL | |
| 5 mM | 0.5109 mL | 2.5545 mL | 5.1089 mL | |
| 10 mM | 0.2554 mL | 1.2772 mL | 2.5545 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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