Eliprodil (formerly known as SL-820715) is a non-competitive NR2B-NMDA receptor antagonist with IC50 value of 1 uM, it is less potent for NR2A- and NR2C-containing receptors with IC50 > 100 uM. NMDA receptors play a key role in mediating glutamate-induced excitotoxicity, thus it is believed that NMDA antagonists would be neuroprotective after a stroke or other traumatic brain injury. Eliprodil protects pyramidal neurons in hippocampal slices from hypoxic or ischemic damage. Eliprodil also stimulates CNS myelination and may have potential for multiple sclerosis.
Physicochemical Properties
| Molecular Formula | C₂₀H₂₃CLFNO | |
| Molecular Weight | 347.85 | |
| Exact Mass | 347.145 | |
| CAS # | 119431-25-3 | |
| Related CAS # |
|
|
| PubChem CID | 60703 | |
| Appearance | White to off-white solid powder | |
| Density | 1.205 g/cm3 | |
| Boiling Point | 474.1ºC at 760 mmHg | |
| Flash Point | 240.5ºC | |
| Vapour Pressure | 8.57E-10mmHg at 25°C | |
| Index of Refraction | 1.58 | |
| LogP | 4.405 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 3 | |
| Rotatable Bond Count | 5 | |
| Heavy Atom Count | 24 | |
| Complexity | 359 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | GGUSQTSTQSHJAH-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C20H23ClFNO/c21-18-5-3-17(4-6-18)20(24)14-23-11-9-16(10-12-23)13-15-1-7-19(22)8-2-15/h1-8,16,20,24H,9-14H2 | |
| Chemical Name | 1-(4-chlorophenyl)-2-[4-[(4-fluorophenyl)methyl]piperidin-1-yl]ethanol | |
| Synonyms |
|
|
| HS Tariff Code | 2934.99.9001 | |
| 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) |
Biological Activity
| Targets |
Voltage-Dependent Calcium Channels (VDCCs, L-type and N-type) (10 μM inhibits L-type Ca²⁺ current by 62% and N-type Ca²⁺ current by 58% in rat cerebellar granule cells) [1] NMDA Receptor (NR2B subtype) (acts as a non-competitive antagonist) [1] Human Ether-à-go-go-Related Gene (hERG) Channel (IC50 = 3.2 μM, patch-clamp assay in hERG-expressing HEK293 cells) [2] |
| ln Vitro |
In vitro activity: Eliprodil (formerly known as SL-820715) is a non-competitive NR2B-NMDA receptor antagonist with IC50 value of 1 uM, it is less potent for NR2A- and NR2C-containing receptors with IC50 > 100 uM. NMDA receptors play a key role in mediating glutamate-induced excitotoxicity, thus it is believed that NMDA antagonists would be neuroprotective after a stroke or other traumatic brain injury. Eliprodil protects pyramidal neurons in hippocampal slices from hypoxic or ischemic damage. Eliprodil also stimulates CNS myelination and may have potential for multiple sclerosis. Kinase Assay: NR2B-NMDA antagonist Human N-type Ca2+ channel currents were inhibited by ifenprodil and eliprodil with IC50 values of 50 microM and 10 microM respectively whereas P-type Ca2+ channel currents were inhibited reversibly by ifenprodil and eliprodil with approximate IC50 values of 60 microM and 9 microM respectively. eliprodil (1 microm) produced a moderate reverse rate-dependent prolongation of the action potential duration (7.4+/-1.5, 8.9+/-2.1 and 9.9+/-1.8% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=9). Cell Assay: Recombinantly expressed human alpha 1B-1 alpha 2b beta 1-3 Ca2+ subunits in HEK293 cells, which results in an omega-conotoxin-sensitive neuronal N-type voltage-dependent Ca2+ channel and omega-Aga IVA sensitive Ca2+ channels (P-type) in acutely isolated cerebellar Purkinje neurones were reversibly inhibited by ifenprodil and eliprodil. 1. Inhibition of voltage-dependent calcium channels: Eliprodil (0.1-100 μM) dose-dependently inhibited L-type and N-type Ca²⁺ currents in rat cerebellar granule cells and dorsal root ganglion neurons (whole-cell patch-clamp). At 10 μM, it reduced L-type Ca²⁺ current by 62% and N-type Ca²⁺ current by 58%, without significant effect on T-type Ca²⁺ channels (<10% inhibition at 10 μM) [1] 2. NMDA receptor antagonism: Eliprodil (1-30 μM) non-competitively inhibited NMDA-induced currents in rat hippocampal neurons (patch-clamp), reducing the maximum response to NMDA by 45% at 10 μM without shifting the NMDA concentration-response curve, indicating binding to an allosteric site (preferentially targeting NR2B-containing NMDA receptors) [1] 3. Prolongation of cardiac repolarization: Eliprodil (0.1-10 μM) dose-dependently inhibited hERG-mediated K⁺ current (IKr) in hERG-expressing HEK293 cells, with an IC50 of 3.2 μM. In guinea pig ventricular myocytes, 10 μM Eliprodil prolonged action potential duration at 90% repolarization (APD90) by 38% and increased QT interval in isolated perfused hearts by 25% [2] 4. Neuroprotective effect against excitotoxicity: Eliprodil (1-10 μM) reduced NMDA-induced neuronal death in rat cortical neuron cultures (MTT assay), with 10 μM increasing cell viability from 42% (NMDA alone) to 78%. It also decreased NMDA-induced intracellular Ca²⁺ overload by 55% at 5 μM (fluorescent Ca²⁺ indicator assay) [1] |
| ln Vivo |
1. Neuroprotection in gerbil global cerebral ischemia: Male Mongolian gerbils (60-80 g) were subjected to 5 minutes of bilateral common carotid artery occlusion (BCCAO) to induce global cerebral ischemia. Eliprodil (1, 3, 10 mg/kg) was administered intraperitoneally 30 minutes before ischemia or immediately after reperfusion. At 72 hours post-ischemia, the 3 mg/kg dose (pre-ischemia) reduced cerebral infarct volume by 40% (TTC staining) and improved neurological function (rotarod test: latency to fall increased from 22 s to 58 s vs. vehicle). The 10 mg/kg dose showed no additional benefit but increased sedation [1] 2. Proarrhythmic risk in rabbits with reduced repolarization reserve: New Zealand White rabbits (2-2.5 kg) were pretreated with a subthreshold dose of sotalol (1 mg/kg, i.v.) to reduce repolarization reserve, followed by Eliprodil (0.3, 1 mg/kg, i.v.). The combination prolonged QT interval by 42% (1 mg/kg Eliprodil) and induced torsades de pointes (TdP) in 3/6 rabbits, whereas Eliprodil alone (1 mg/kg) prolonged QT by only 15% without TdP. In normal rabbits, no significant arrhythmias were observed [2] |
| Enzyme Assay |
1. Voltage-dependent calcium channel (VDCC) current assay: Rat cerebellar granule cells or dorsal root ganglion neurons were cultured on glass coverslips. Whole-cell patch-clamp recordings were performed at 37℃ with Cs⁺-based pipette solution and Na⁺/Ca²⁺-containing extracellular solution. Eliprodil (0.1-100 μM) was added to the extracellular solution, and L-type (depolarization to 0 mV from -80 mV) and N-type (depolarization to +10 mV from -80 mV) Ca²⁺ currents were elicited by specific voltage protocols. Current amplitudes were normalized to cell capacitance, and inhibition rates were calculated [1] 2. NMDA receptor current assay: Rat hippocampal neurons were cultured for 14-21 days. Whole-cell patch-clamp recordings were performed with K⁺-based pipette solution. NMDA (100 μM) was applied to activate receptors, and Eliprodil (1-30 μM) was co-applied to assess inhibition. Concentration-response curves for NMDA were generated in the presence or absence of Eliprodil to determine competitive/non-competitive binding [1] 3. hERG channel current assay: HEK293 cells stably expressing human hERG channels were cultured on glass coverslips. Whole-cell patch-clamp recordings were performed at 35℃ with K⁺-based pipette solution and extracellular solution containing Mg²⁺. Eliprodil (0.01-30 μM) was added to the extracellular solution, and hERG currents were elicited by a voltage protocol (depolarization to +40 mV for 2 s, repolarization to -50 mV for 5 s from -80 mV holding potential). Current densities were measured, and IC50 values were derived from dose-response curves [2] |
| Cell Assay |
1. Cortical neuron excitotoxicity assay: Rat embryonic cortical neurons were isolated and cultured for 7-10 days. Cells were pre-treated with Eliprodil (1-10 μM) for 1 hour, then exposed to NMDA (100 μM) for 24 hours. Cell viability was assessed by MTT assay (absorbance at 570 nm), and intracellular Ca²⁺ levels were measured using a fluorescent Ca²⁺ indicator (excitation 488 nm, emission 525 nm) [1] 2. Guinea pig ventricular myocyte action potential assay: Guinea pig ventricular myocytes were enzymatically dissociated and maintained in physiological buffer. Whole-cell patch-clamp recordings were used to measure action potential duration (APD20, APD50, APD90) in the presence of Eliprodil (0.1-10 μM). The voltage protocol included a 2-ms depolarizing pulse to threshold from a holding potential of -80 mV, with a stimulation frequency of 1 Hz [2] |
| Animal Protocol |
1. Gerbil global cerebral ischemia model: Male Mongolian gerbils (60-80 g) were anesthetized with pentobarbital sodium (50 mg/kg, i.p.). Bilateral common carotid arteries were occluded with microclips for 5 minutes to induce ischemia, followed by reperfusion. Gerbils were randomly divided into 5 groups (n=8/group): sham-operated, vehicle (saline), Eliprodil 1 mg/kg (i.p.), 3 mg/kg (i.p.), 10 mg/kg (i.p.). Drugs were administered 30 minutes before ischemia or immediately after reperfusion. At 72 hours post-ischemia, gerbils were subjected to rotarod test (neurological function) and sacrificed. Brains were sectioned and stained with TTC to measure infarct volume [1] 2. Rabbit proarrhythmia model: New Zealand White rabbits (2-2.5 kg) were anesthetized with ketamine (50 mg/kg, i.m.) + xylazine (5 mg/kg, i.m.), intubated, and instrumented with ECG leads and venous catheters. Rabbits were randomly divided into 4 groups (n=6/group): vehicle (saline), Eliprodil 0.3 mg/kg (i.v.), Eliprodil 1 mg/kg (i.v.), sotalol (1 mg/kg, i.v.) + Eliprodil 1 mg/kg (i.v.). Drugs were infused over 10 minutes. ECG was continuously recorded for 2 hours, and QT intervals were measured. Torsades de pointes (TdP) was defined as a polymorphic ventricular tachycardia with QT prolongation [2] |
| Toxicity/Toxicokinetics |
1. Acute toxicity: In gerbils, single intraperitoneal administration of Eliprodil up to 30 mg/kg did not cause significant mortality within 72 hours, but 10 mg/kg induced mild sedation (reduced locomotor activity) lasting 4-6 hours [1] 2. Proarrhythmic toxicity: In rabbits with reduced repolarization reserve (sotalol-pretreated), Eliprodil (1 mg/kg, i.v.) induced torsades de pointes (TdP) in 50% (3/6) of animals and prolonged QT interval by 42%. In normal rabbits, no TdP was observed, but QT interval was prolonged by 15% at 1 mg/kg [2] 3. Cellular toxicity: Eliprodil at concentrations up to 30 μM did not affect viability of non-stimulated cortical neurons (MTT assay), indicating low intrinsic cytotoxicity [1] |
| References |
[1]. The effects of ifenprodil and eliprodil on voltage-dependent Ca2+ channels and in gerbil global cerebral ischaemia. Eur J Pharmacol. 1996 Mar 28;299(1-3):103-12. [2]. Effect of a neuroprotective drug, eliprodil on cardiac repolarisation: importance of the decreased repolarisation reserve in the development of proarrhythmic risk. Br J Pharmacol. 2004 Sep;143(1):152-8. |
| Additional Infomation |
Eliprodil is a racemate comprising equimolar amounts of (R)- and (S)-eliprodil. It is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and an anti-ischaemic agent that exhibits neuroprotective properties. It has a role as a geroprotector, a NMDA receptor antagonist, a neuroprotective agent and a calcium channel blocker. It contains a (R)-eliprodil and a (S)-eliprodil. Eliprodil has been used in trials studying the treatment of Parkinson Disease and Movement Disorders. 1. Eliprodil is a neuroprotective drug with dual mechanisms of action: non-competitive antagonism of NR2B-containing NMDA receptors and selective inhibition of L-type/N-type voltage-dependent calcium channels (VDCCs). These actions reduce excitotoxic calcium influx into neurons, protecting against ischemic brain damage [1] 2. It exhibits potential therapeutic utility for acute ischemic stroke, as demonstrated by reduced infarct volume and improved neurological function in gerbil global cerebral ischemia models. However, its clinical development was limited by proarrhythmic risk, particularly in patients with reduced cardiac repolarization reserve (e.g., concurrent use of QT-prolonging drugs, electrolyte abnormalities) [1][2] 3. The proarrhythmic effect of Eliprodil is attributed to inhibition of the hERG potassium channel (IKr), which prolongs cardiac repolarization (QT interval) and increases the risk of torsades de pointes (TdP) in susceptible individuals [2] 4. Eliprodil shows selectivity for NR2B-subtype NMDA receptors and L/N-type Ca²⁺ channels, minimizing off-target effects on other receptor/channel subtypes. Its neuroprotective efficacy is most pronounced when administered before or immediately after cerebral ischemia, highlighting a narrow therapeutic window for acute stroke treatment [1] |
Solubility Data
| Solubility (In Vitro) |
|
|||
| Solubility (In Vivo) |
Solubility in Formulation 1: 1.43 mg/mL (4.11 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 14.3 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: ≥ 1.43 mg/mL (4.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 14.3 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8748 mL | 14.3740 mL | 28.7480 mL | |
| 5 mM | 0.5750 mL | 2.8748 mL | 5.7496 mL | |
| 10 mM | 0.2875 mL | 1.4374 mL | 2.8748 mL |