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| Targets |
Mirogabalin targets the α2δ-1 and α2δ-2 subunits of voltage-gated calcium channels. As a preferentially selective α2δ-1 ligand, mirogabalin binds with high potency and selectivity to the α2δ-1 subunit of voltage-sensitive calcium-channel complexes in the CNS. By binding to the α2δ subunit, mirogabalin modulates the function of voltage-gated calcium channels, reducing the release of excitatory neurotransmitters such as glutamate, substance P, and calcitonin gene-related peptide. This mechanism contributes to its analgesic effects in neuropathic pain. Mirogabalin is a third-generation gabapentinoid with improved potency and selectivity compared to earlier compounds such as gabapentin and pregabalin. The compound's selectivity for α2δ-1 over α2δ-2 contributes to its efficacy and safety profile.
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| ln Vitro |
Mirogabalin (DS-5565) is a newly developed, highly potent, and selective α2δ-1 ligand for the α2δ-1 subunit of the voltage-sensitive calcium channel complex in the central nervous system (CNS). Milopalin dissociates from α2δ-1 more slowly than α2δ-2 and, in particular, α2δ-1 more slowly than pregabalin, according to in vitro investigations conducted with membrane preparations from human and rat α2δ subunit-expressing cells. In addition, compared to pregabalin, milopalin showed greater analgesic efficacy and broader central nervous system safety while demonstrating strong and prolonged analgesia in streptozotocin-induced diabetic rats. Its selectivity for α2δ-1 and slower dissociation as compared to pregabalin are the reasons for the range [1]. DS-5565, an α2δ-1 ligand, is being developed to treat postherpetic neuralgia, fibromyalgia, and diabetic peripheral neuropathy pain. Milopalin specifically targets α2δ-1, an auxiliary protein linked to voltage-sensitive calcium channel complexes in the brain. Numerous pain neurotransmitters are released less often as a result of this binding's reduction of calcium input into nerve terminals. Milopaline's estimated ED50 (converted scale) is 20.5 mg, with a 90% confidence interval (CI) ranging from 10.1-41.7 mg [2].
In vitro, mirogabalin demonstrates potent and selective binding to the α2δ-1 subunit of voltage-gated calcium channels. Mirogabalin is a newly developed, highly potent, and selective α2δ-1 ligand for the α2δ-1 subunit of the voltage-sensitive calcium channel complex in the central nervous system. It binds to the α2δ-1 and α2δ-2 subunits of voltage-dependent Ca²⁺ channels. In cellular assays, mirogabalin's effects on calcium influx and neurotransmitter release can be assessed. The compound's selectivity for α2δ subunits over other calcium channel subunits contributes to its efficacy and safety profile. Mirogabalin's in vitro activity supports its use as an analgesic for neuropathic pain. |
| ln Vivo |
Furthermore, milopalin demonstrated strong and long-lasting analgesic effects in streptozotocin-induced diabetic rats. Its selectivity for α2δ-1 and slow dissociation are responsible for its superior analgesic efficacy and wider central nervous system (CNS) effects as compared to pregabalin safety margin. In contrast to pregabalin [1].
In vivo, mirogabalin demonstrates potent and sustained analgesic effects in various animal models of pain. Mirogabalin has potent and sustained analgesic effects with an ED₅₀ of 2.5 mg/kg. The compound is being developed for pain associated with diabetic peripheral neuropathy, fibromyalgia, and postherpetic neuralgia. Mirogabalin is a calcium channel blocker with analgesic effects. The compound's in vivo efficacy in pain models supports its clinical development for neuropathic pain. Mirogabalin has been approved in Japan for the treatment of neuropathic pain. |
| Enzyme Assay |
In vitro binding assays for mirogabalin employ radioligand displacement techniques using membrane preparations from cells or tissues expressing α2δ subunits. The assay involves incubating mirogabalin at varying concentrations with the membrane preparation and a fixed concentration of a radiolabeled α2δ ligand, such as [³H]-gabapentin. Following incubation, bound and free radioligand are separated by rapid filtration, and radioactivity is measured. Non-specific binding is determined in the presence of a high concentration of an unlabeled α2δ ligand. Binding affinity (Kd) values are calculated from saturation or competition curves using nonlinear regression analysis. For functional assays, cells expressing voltage-gated calcium channels are used, and calcium influx is measured using fluorescent indicators.
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| Cell Assay |
In vitro cellular assays for mirogabalin employ neuronal cell lines or primary neurons expressing voltage-gated calcium channels. Cells are cultured in appropriate media and treated with mirogabalin at various concentrations. Calcium influx is measured using fluorescent indicators such as Fura-2 or Fluo-4 following depolarization. Neurotransmitter release is measured by HPLC or ELISA. The compound's effects on cell viability and proliferation can be assessed using standard cytotoxicity assays. The compound's selectivity for α2δ-1 over α2δ-2 can be confirmed by testing against both subunits.
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| Animal Protocol |
In vivo animal experiments for mirogabalin employ models of neuropathic pain. For studies investigating neuropathic pain, animal models such as the spinal nerve ligation model, streptozotocin-induced diabetic neuropathy model, or postherpetic neuralgia model are used. Mirogabalin is administered orally, and pain behaviors such as mechanical allodynia and thermal hyperalgesia are assessed. For pharmacokinetic studies, blood samples are collected at various time points, and mirogabalin concentrations are measured by LC-MS/MS. Dosing regimens vary depending on the experimental objectives.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of mirogabalin have been characterized in clinical studies. Mirogabalin is rapidly absorbed, with a median time to maximum plasma concentration of 1 hour, and rapidly eliminated, with a mean elimination half-life of 2 to 3 hours. Single-dose mirogabalin pharmacokinetic parameters were comparable between Asian and white subjects. Maximum plasma concentration is achieved in less than 1 hour. The plasma protein binding is relatively low, at less than 25%. Mirogabalin is primarily excreted unchanged in the urine, and the administration dose should be adjusted according to renal function. Mirogabalin has a molecular weight of 209.28-209.29 and a molecular formula of C₁₂H₁₉NO₂.
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| Toxicity/Toxicokinetics |
The toxicity profile of mirogabalin is consistent with that of gabapentinoids. Common adverse effects include somnolence, dizziness, headache, and peripheral edema. The compound should be used with caution in patients with renal impairment, as dose adjustment is required. Mirogabalin has been approved in Japan for the treatment of neuropathic pain. The compound's safety in pregnancy and lactation has not been established, and its use should be guided by clinical judgment.
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| References |
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| Additional Infomation |
Mirogabalin has been used in clinical trials for the treatment of postherpetic neuralgia, fibromyalgia-related pain, and diabetic peripheral neuropathy pain. See also: Mirogabalin benzylsulfonate (note moved to).
Mirogabalin is a novel, preferentially selective α2δ-1 ligand with high potency and selectivity for the α2δ-1 subunit of voltage-sensitive calcium-channel complexes in the CNS. It is a third-generation gabapentinoid and a selective ligand for the α2δ subunit of VGCCs. Mirogabalin binds to the α2δ-1 and α2δ-2 subunits of voltage-dependent Ca²⁺ channels. It has potent and sustained analgesic effects (ED₅₀ = 2.5 mg/kg). Mirogabalin is rapidly absorbed with a median T_max of 1 hour and a mean elimination half-life of 2 to 3 hours. Mirogabalin has a molecular weight of 209.28-209.29 and a molecular formula of C₁₂H₁₉NO₂. It is developed for neuropathic pain. |
| Molecular Formula |
C12H19NO2
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| Molecular Weight |
209.2848
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| Exact Mass |
209.142
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| CAS # |
1138245-13-2
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| Related CAS # |
1138245-21-2 (besylate);1138245-13-2;
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| PubChem CID |
59509752
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| Appearance |
Light yellow to light brown solid powder
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| LogP |
2.482
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
15
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| Complexity |
311
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| Defined Atom Stereocenter Count |
3
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| SMILES |
CCC1=C[C@@H]2[C@H](C1)C[C@@]2(CC(=O)O)CN
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| InChi Key |
FTBQORVNHOIASH-CKYFFXLPSA-N
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| InChi Code |
InChI=1S/C12H19NO2/c1-2-8-3-9-5-12(7-13,6-11(14)15)10(9)4-8/h4,9-10H,2-3,5-7,13H2,1H3,(H,14,15)/t9-,10-,12-/m1/s1
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| Chemical Name |
2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid
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| Synonyms |
DS-5565 DS 5565 DS5565 A-2000700 A2000700A 2000700Mirogabalin besylate Mirogabalin free base.
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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) |
H2O : ~7.71 mg/mL (~36.84 mM)
DMSO :< 1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.83 mg/mL (3.97 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 8.3 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: ≥ 0.83 mg/mL (3.97 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 8.3 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: ≥ 0.83 mg/mL (3.97 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 10 mg/mL (47.78 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.7783 mL | 23.8914 mL | 47.7829 mL | |
| 5 mM | 0.9557 mL | 4.7783 mL | 9.5566 mL | |
| 10 mM | 0.4778 mL | 2.3891 mL | 4.7783 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.
Link: https://clinicaltrials.gov/ct2/show/NCT07451431
Conditions:Diabetic Peripheral Neuropathic Pain (DPNP)Link: https://clinicaltrials.gov/ct2/show/NCT07157852
Conditions:Fibromyalgia|Pregabalin|Mirogabalin|PainLink: https://clinicaltrials.gov/ct2/show/NCT06328062
Conditions:Pain Postoperative|Osteoarthritis|Total Knee Arthroplasty
Title:Comparison of the Efficacy and Safety of Mirogabalin and Duloxetine in Chemotherapy-induced Peripheral Neuropathy in a Randomized Controlled Trial: a Quality of Life Study in Cancer Survivors
Status:Not yet recruiting
updateDate:2024-12-02
Ctid:NCT06711978
Link: https://clinicaltrials.gov/ct2/show/NCT06711978
Conditions:CIPN|CIPN - Chemotherapy-Induced Peripheral Neuropathy|CIPN in Adjuvant Breast Cancer Patients|Duloxetine|MirogabalinLink: https://clinicaltrials.gov/ct2/show/NCT03901352
Conditions:Central Neuropathic PainLink: https://clinicaltrials.gov/ct2/show/NCT04094662
Conditions:Diabetic Peripheral Neuropathic PainLink: https://rctportal.mhlw.go.jp/en/detail?trial_id=jRCT1080223624
Condition:Healthy volunteersLink: https://rctportal.mhlw.go.jp/en/detail?trial_id=jRCT2080223005
Condition:Diabetic peripheral neuropathic pain, Post-herpetic neuralgiaLink: https://rctportal.mhlw.go.jp/en/detail?trial_id=jRCT2080222129
Condition:Japanese Subjects with varying degrees of renal functionProducts are for research use only; We do not sell to patients
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