| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg |
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| 10mg | |||
| Other Sizes |
| Targets |
Ki: 5.1±1.2 nM (rat GABAB), 1.4±0.3 μM (rat GABAA)[1] EC50: 8.6±0.77 nM (human GABAB receptor)[1]
GABA receptor type B. Lesogaberan is a potent and selective GABAB receptor agonist. It acts as a full agonist, primarily targeting peripheral GABAB receptors. In vitro, it has an EC50 of 8.6 nM for the human recombinant GABAB receptor. It shows negligible activity at the GABAA receptor. |
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| ln Vitro |
Human islet cell proliferation is enhanced in vitro by leogaberan hydrochloride (3–30 nM)[2].
In vitro, Lesogaberan is a potent and selective full agonist of the GABAB receptor, with an EC50 of 8.6 nM for the human recombinant receptor. This high potency and selectivity for GABAB over GABAA is a defining characteristic of its in vitro pharmacological profile. |
| ln Vivo |
In dogs, lesogaberan hydrochloride shows a biphasic dose-response curve that potently activates recombinant human GABAB receptors and inhibits transient lower esophageal sphincter relaxation (TLESR)[1]. Apoptosis of human islet β-cells in islet grafts in mice is prevented by oral Lesogaberan hydrochloride (0.08 mg/mL; 48 hours)[2]. Sprague-Dawley female rats exhibit relatively low systemic clearance and high oral availability (88% in the dog and 100% in the rat) when given lesogaberan (7 μmol/kg) hydrochloride[1].
In vivo, Lesogaberan is developed as a peripherally acting GABAB receptor agonist. It potently inhibits transient lower esophageal sphincter relaxations (TLESRs), the primary mechanism behind gastroesophageal reflux disease (GERD). It decreases the number of acid reflux events and improves acid exposure time in the distal esophagus. Lesogaberan does not readily penetrate the CNS, limiting sedative side effects. |
| Enzyme Assay |
The binding affinity (Ki) of Lesogaberan can be measured via a non-cellular competition assay. Rat brain membranes are incubated with [3H]GABA and varying concentrations of Lesogaberan. Separation of bound and free ligand by filtration allows for the calculation of Ki for the GABAB site, demonstrating its high affinity for the native receptor.
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| Cell Assay |
Cell Proliferation Assay[2]
Cell Types: Human islet cells Tested Concentrations: 3, 10, and 30 nM Incubation Duration: 4 days Experimental Results: Had a small but nonsignificant promitotic effect at 3 nM, while treatment at higher dosages (10 and 30 nM) led to a 2-3-fold increase in proliferation relative to that of islets cultured in medium alone. To confirm functional selectivity for GABAB over GABAA, a cellular assay can be performed. HEK-293 cells expressing the human GABAB receptor (GB1/GB2 heterodimer) are used for one assay, while cells expressing GABAA are used for another. Cells are loaded with a calcium-sensitive dye. Lesogaberan is applied, and the resulting fluorescence change (due to G-protein activation) is measured to determine EC50 at the B receptor. The lack of signal in GABAA cells confirms selectivity. |
| Animal Protocol |
Animal/Disease Models: Diabetic NOD/SCID (severe combined immunodeficient) mouse were implanted with human islets[2]
Doses: 0.08 mg/mL Route of Administration: 48 hrs (hours) Experimental Results: Dramatically decreased the percentages of apoptotic islet cells and increased the frequency of insulin+ β-cells in human islet grafts. Animal/Disease Models: Female Sprague Dawley rats[1] Doses: 7 μmol/kg (pharmacokinetic/PK Analysis) Route of Administration: Oral Experimental Results: High oral availability (88% in the dog and 100% in the rat) and relatively low systemic clearance. Plasma protein binding was 1% in rat and human plasma. A standard in vivo model for Lesogaberan is measuring TLESRs in dogs. Beagle dogs are surgically fitted with a gastric cannula and a manometric catheter to measure lower esophageal sphincter pressure. Lesogaberan is administered orally, and the number of TLESRs is counted over a period of 2-3 hours post-dose, comparing to vehicle and positive control (baclofen). |
| ADME/Pharmacokinetics |
In humans, Lesogaberan is rapidly and extensively absorbed from the GI tract, with Cmax achieved within 1-2 hours of oral dosing. The terminal half-life is between 11 and 13 hours. Orally administered Lesogaberan has high bioavailability, and the majority of the dose is excreted by the kidneys either as parent compound or as metabolites.
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| Toxicity/Toxicokinetics |
No detailed toxicology data is provided. A key feature of Lesogaberan is its reduced CNS side-effect profile. Because it is a peripherally restricted GABAB agonist due to active transport out of the CNS, it was developed to avoid the dose-limiting CNS side effects (e.g., sedation, confusion) seen with centrally penetrating GABAB agonists like baclofen.
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| References |
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| Additional Infomation |
Lesogaberan (AZD3355) was a clinical drug candidate developed by AstraZeneca as an add-on treatment to proton-pump inhibitors (PPIs) for patients with GERD. The drug progressed into Phase II clinical trials but was ultimately discontinued, possibly due to a lack of sufficient efficacy despite a clean safety profile. It represents a classical case of a “peripheral restriction” drug design strategy.
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| Molecular Formula |
C3H9CLFNO2P
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|---|---|
| Molecular Weight |
176.534224271774
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| Exact Mass |
176.004
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| CAS # |
2925644-17-1
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| Related CAS # |
Lesogaberan;344413-67-8;Lesogaberan napadisylate;477956-38-0
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| PubChem CID |
162640398
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| Appearance |
Colorless to light yellow viscous liquid
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
9
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| Complexity |
89.4
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| Defined Atom Stereocenter Count |
1
|
| SMILES |
Cl.[P+](C[C@@H](CN)F)(=O)O
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| InChi Key |
CJVIVHIKWIZWOJ-AENDTGMFSA-O
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| InChi Code |
InChI=1S/C3H7FNO2P.ClH/c4-3(1-5)2-8(6)7;/h3H,1-2,5H2;1H/p+1/t3-;/m1./s1
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| Chemical Name |
[(2R)-3-amino-2-fluoropropyl]-hydroxy-oxophosphanium;hydrochloride
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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: 240 mg/mL (1351.81 mM)
H2O: 100 mg/mL (563.25 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 6 mg/mL (33.80 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 60.0 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: ≥ 6 mg/mL (33.80 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 60.0 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: ≥ 6 mg/mL (33.80 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: 100 mg/mL (563.25 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 | 5.6648 mL | 28.3238 mL | 56.6476 mL | |
| 5 mM | 1.1330 mL | 5.6648 mL | 11.3295 mL | |
| 10 mM | 0.5665 mL | 2.8324 mL | 5.6648 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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