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MRGPRX1 agonist 1 is a novel and highly potent agonist of MRGPRX1 (Mas-related G-protein-coupled receptor X1) (EC50 = 50 nM) with analgesic effects. MRGPRX1 is a receptor specific to human sensory neurons that is being actively studied as a potential therapeutic target for the management of pain..
| Targets |
MRGPRX1 ( EC50 = 50 nM )
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|---|---|
| ln Vivo |
Human homologue MRGPRX1 has gained increased interest as a promising therapeutic target partly owing to the analgesic effects of BAM8-22.A proteolytic product derived from proenkephalin A with full agonist activity at human MRGPRX1 and its closest rodent orthologues, mouse MRGPRC11 and rat MRGPRC. For example, intrathecal (spinal cord) injection of BAM8-22 was found to attenuate both mechanical and thermal hyperalgesia in mice4 and rats.We have also found that JHU-58 , an Arg-Phe-NH2 peptidomimetic with full agonist activity at mouse MRGPRC11 and rat MRGPRC,6 exhibits analgesic effects in rodent models of neuropathic pain.5 JHU-58, however, displayed negligible agonist activity at human MRGPRX1, hindering its ability to serve as a molecular template for further structural optimization efforts aimed at clinical translation. Human MRGPRX1 agonists 1 and 2 reported by GSK7 and ACADIA,8 respectively, may have a potential to be explored as new leads though their high molecular weight (>500) likely contributes to unfavorable CNS drug-like molecular properties and solubility. Indeed, compound 1 could not be tested in vitro at concentrations above 2 μM due to its limited solubility.
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| Cell Assay |
In Vitro MrgV1 receptor assay.
HEK293 cells stably transfected with human MrgprX1 were plated in 96 well plates at 25,000 cell/well and incubated 2 days before imaging. On the day of imaging cells were incubated in 100 μL HBSS with 2 μM Fluo 4AM and 1% Trypan Red for 50 minutes at 37°C. The cells were then equilibrated for 10 minutes at room temperature before imaging. Test compounds were dissolved in HBSS and diluted in a serial dilution. Test compounds, BAM 8–22 (positive control) or HBSS (negative control) were added (50 μL into 100 μL) and cells were imaged on the FLIPR for 2 minutes. Data was exported as maximum – minimum fluorescent signal.[1] Whole-cell recordings of cultured DRG neurons. Whole cell currents of cultured DRG neurons from MrgprX1 mice with MrgprA3-GFP marker were recorded with an Axon 700B amplifier and pCLAMP 9.2 software. Extracellular solution contained (in mM) 130 N-methyl-D-glucamine chloride (NMDG-Cl), 5 BaCl2, 1 MgCl2, 10 HEPES, and 10 glucose, with pH of 7.4 adjusted with 1 M NMDG. Osmolality was adjusted to 310 mOsm/kg with sucrose. Electrodes were pulled from borosilicate glass with resistances of 2–4 MΩ. Pipette solution contained (in mM) 140 tetraethylammonium chloride, 10 EGTA, 1 MgCl2, 10 HEPES, 0.5 GTP, and 3 ATP, with pH of 7.4 and osmolality of approximately 300 mOsm/kg. The voltage protocol was modified from a previously published method.3 Briefly, cells were held at −80 mV and evoked to −40 mV for 20 milliseconds (ms) to activate low-voltage Ca2+ channels, and then held to −60 mV for 20 ms and evoked to −10 mV for 40 ms to activate HVA Ca2+ channels. Leak currents were subtracted with P/4 protocol. Liquid junction potentials and whole cell capacitances were offset, and series resistances were compensated by 70%. All experiments were performed at room temperature (21–23°C).[1] |
| Animal Protocol |
DRG sensory neuronal cultures.
DRGs from 3–4-week-old MrgprX1 mice were collected in cold DH10 medium (DMEM/F-12 with 10% fetal bovine serum and 1% penicillin/streptomycin, Gibco) and treated with enzyme solution (5 mg/mL dispase and 1 mg/mL collagenase Type I in HBSS without Ca2+ and Mg2+, Gibco) at 37°C. After trituration and centrifugation, cells were re-suspended in DH10 with nerve growth factor (50 ng/mL, Upstate Biotechnology, Lake Placid, NY) and glial cell line-derived neurotrophic factor (25 ng/mL, R&D Systems), plated on glass coverslips coated with poly-D-lysine (100 μg/mL, Biomedical Technologies) and laminin (10 μg/mL, Invitrogen), cultured at 37°C, and used after 20–40 hours.[1] |
| References |
| Molecular Formula |
C23H21N3O4S
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|---|---|
| Molecular Weight |
435.495544195175
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| Exact Mass |
435.13
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| Elemental Analysis |
C, 63.43; H, 4.86; N, 9.65; O, 14.69; S, 7.36
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| CAS # |
2377379-39-8
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| Related CAS # |
2377379-39-8
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| PubChem CID |
139030531
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| Appearance |
White to yellow solid powder
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| LogP |
4.1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
31
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| Complexity |
685
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
BWEJNHRMGZUMNU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H21N3O4S/c1-15-7-10-19(26-31(27,28)22-6-4-3-5-20(22)29-2)21(13-15)30-17-8-9-18-16(14-17)11-12-25-23(18)24/h3-14,26H,1-2H3,(H2,24,25)
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| Chemical Name |
N-[2-(1-aminoisoquinolin-6-yl)oxy-4-methylphenyl]-2-methoxybenzenesulfonamide
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| Synonyms |
BUN-79398; BUN 79398; BUN79398; MRGPRX1 agonist 1
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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 (~287.0 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.78 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 (4.78 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 (4.78 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 | 2.2962 mL | 11.4811 mL | 22.9621 mL | |
| 5 mM | 0.4592 mL | 2.2962 mL | 4.5924 mL | |
| 10 mM | 0.2296 mL | 1.1481 mL | 2.2962 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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