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GV-58 is a pupin analog that acts as a novel, potent and selective agonist of N- and P/Q-type Ca2+ channels with EC50 of 7.21/8.81 uM for N-type/P-Q-type Ca2+ channel. It has the potential to be used for treating neuromuscular weakness.
| Targets |
N-type (Cav2.2) calcium channels (EC50 = 7.21 ± 0.86 µM)
P/Q-type (Cav2.1) calcium channels (EC50 = 8.81 ± 1.07 µM) Cyclin-dependent kinase 1 (Cdk1) (IC50 >20 µM) Cyclin-dependent kinase 2 (Cdk2) (IC50 = 3.29 ± 0.43 µM) Cyclin-dependent kinase 5 (Cdk5) (IC50 = 3.03 ± 0.32 µM) No agonist activity on L-type (Cav1.3) calcium channels up to 100 µM. [1] |
|---|---|
| ln Vitro |
The ability of LEMS to passively transfer neuromuscular junctions is restored by GV-58 (50 μM; 30 minutes) [1].
In whole-cell patch-clamp recordings using tsA-201 cells expressing N-type (Cav2.2) calcium channels, GV-58 increased the tail current integral by approximately 32-fold compared to control, with an EC50 of 7.21 ± 0.86 µM. [1] In tsA-201 cells expressing P/Q-type (Cav2.1) calcium channels, GV-58 increased the tail current integral by approximately 33-fold compared to control, with an EC50 of 8.81 ± 1.07 µM. [1] In a commercial kinase screen, GV-58 showed reduced inhibitory activity against Cdks compared to (R)-roscovitine, with IC50 values of >20 µM for Cdk1, 3.29 ± 0.43 µM for Cdk2, and 3.03 ± 0.32 µM for Cdk5. No significant inhibition of MAPK1 or MLCK was observed at concentrations up to 20 µM. [1] |
| ln Vivo |
In a passive transfer mouse model of Lambert-Eaton myasthenic syndrome (LEMS), application of 50 µM GV-58 to ex vivo neuromuscular junction (NMJ) preparations significantly increased endplate potential (EPP) amplitude from 13.00 ± 0.56 mV to 19.44 ± 0.98 mV, and quantal content (measured by peak) from 38.0 ± 12.8 to 56.0 ± 15.2. Quantal content measured by EPP area increased from 38.3 ± 12.7 to 65.6 ± 15.0. [1]
GV-58 (50 µM) significantly increased the frequency of miniature endplate potentials (mEPPs) from 3.27 ± 0.15 s⁻¹ to 10.45 ± 0.64 s⁻¹, but did not significantly change mEPP amplitude. [1] GV-58 (50 µM) partially restored short-term plasticity characteristics during a 50 Hz stimulus train in LEMS model NMJs, changing the response from facilitation to a pattern more resembling depression. [1] The potent Cdk inhibitor olomoucine (50 µM) did not significantly increase transmitter release, indicating that the effects of GV-58 are due to Ca²⁺ channel agonism, not Cdk inhibition. [1] |
| Enzyme Assay |
A kinase screen was performed using a commercial service. The inhibitory activity of GV-58 and reference compounds was tested at three concentrations (0.2, 2, and 20 µM) against five kinases: Cdk1/cyclinB, Cdk2/cyclinA, Cdk5/p35, MAPK1, and MLCK. All assays were conducted in the presence of 10 µM ATP. IC50 values were determined from the resulting dose-response curves. [1]
|
| Cell Assay |
Cell Viability Assay[1]
Cell Types: Upper arm muscle isolated from LEMS mice Tested Concentrations: 50 μM Incubation Duration: 30 minutes Experimental Results: mEPP frequency increased from 3.27 s−1 in vehicle control to 10.45 s−1. A slight boost was shown in the final EPP on the train, which subsequently dropped to 94%. Whole-cell perforated patch-clamp recordings were performed to assess calcium channel activity. Pipettes were filled with a solution containing Cs₂SO₄, CsCl, MgCl₂, and HEPES (pH 7.4). Cells were bathed in a saline containing choline chloride, TEA-Cl, CaCl₂, MgCl₂, and HEPES (pH 7.4). Pipette tips were dipped in antibiotic-free solution, then backfilled with solution containing amphotericin-B to achieve perforated patch access. Currents were recorded using an amplifier, filtered at 5 kHz, and digitized at 10 kHz. Tail current integrals were measured before and after compound application, with each trace normalized to its peak. Compounds were bath-applied from DMSO stock solutions. Control experiments with DMSO alone showed no significant effects. [1] |
| Animal Protocol |
A LEMS passive-transfer mouse model was established. Adult female CFW mice received an intraperitoneal injection of cyclophosphamide (300 mg/kg) on day 1 to suppress immune responses. For the next 24-30 consecutive days, mice received daily intraperitoneal injections of either 1.5 ml of serum from LEMS patients or 1.5 ml of control human serum. LEMS patient sera were screened for voltage-gated calcium channel antibodies and for their ability to reduce quantal content in mice. Serum from patient aBC2 was selected for consistent efficacy. [1]
For ex vivo electrophysiology, the epitrochleoanconeus (ETA) muscle with its nerve was dissected after the passive transfer protocol. The preparation was placed in a physiological saline bath. The nerve was stimulated via a suction electrode, and muscle contractions were blocked by μ-conotoxin GIIIB (1 µM). Intracellular recordings were made using microelectrodes filled with potassium acetate. Spontaneous mEPPs and nerve-evoked EPPs (single and 50 Hz trains) were recorded. [1] To test drug effects, baseline recordings were taken in vehicle (0.05–0.1% DMSO), followed by a 30-minute incubation in 50 µM GV-58 and subsequent recordings from the same NMJs. [1] |
| References |
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| Additional Infomation |
GV-58 is a novel (R)-roscovitine analog developed through strategic medicinal chemical modification of the purine backbone, particularly benzylamine and isopropyl side chains, aimed at reducing cyclin-dependent kinase (Cdk) antagonistic activity while enhancing calcium channel agonistic activity. [1] Its primary mechanism of action is as an agonist of presynaptic N-type and P/Q-type voltage-gated calcium channels, slowing channel deactivation mechanics, thereby increasing calcium influx during action potentials and enhancing neurotransmitter release at the synapse. [1] GV-58 has shown promising therapeutic potential in enhancing weakened neuromuscular synapses in Lambert-Eaton myasthenia gravis syndrome (LEMS) and represents a novel strategy for direct targeting of calcium channels, distinct from standard indirect therapy using potassium channel blockers such as 3,4-diaminopyridine. [1] It may also have the potential to treat other neuromuscular diseases characterized by presynaptic weakness, such as certain congenital myasthenia gravis syndromes. [1]
In addition to its therapeutic uses, GV-58 can also serve as an important experimental tool for studying the basic characteristics of P/Q and N-type calcium channels and the regulation of neurotransmitter release by calcium. [1] |
| Molecular Formula |
C₁₈H₂₆N₆OS
|
|---|---|
| Molecular Weight |
374.50
|
| Exact Mass |
374.188
|
| CAS # |
1402821-41-3
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| PubChem CID |
71463101
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| Appearance |
Off-white to light brown solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
599.6±60.0 °C at 760 mmHg
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| Flash Point |
316.4±32.9 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.674
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| LogP |
2.01
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
9
|
| Heavy Atom Count |
26
|
| Complexity |
431
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
CCCN1C=NC2=C(N=C(N=C21)N[C@H](CC)CO)NCC3=CC=C(S3)C
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| InChi Key |
DPTXJOUVBMUSGY-CYBMUJFWSA-N
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| InChi Code |
InChI=1S/C18H26N6OS/c1-4-8-24-11-20-15-16(19-9-14-7-6-12(3)26-14)22-18(23-17(15)24)21-13(5-2)10-25/h6-7,11,13,25H,4-5,8-10H2,1-3H3,(H2,19,21,22,23)/t13-/m1/s1
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| Chemical Name |
(2R)-2-[[6-[(5-methylthiophen-2-yl)methylamino]-9-propylpurin-2-yl]amino]butan-1-ol
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| Synonyms |
GV-58GV 58GV58
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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 : ~75 mg/mL (~200.27 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.68 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 25.0 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: ≥ 2.5 mg/mL (6.68 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 25.0 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 | 2.6702 mL | 13.3511 mL | 26.7023 mL | |
| 5 mM | 0.5340 mL | 2.6702 mL | 5.3405 mL | |
| 10 mM | 0.2670 mL | 1.3351 mL | 2.6702 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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