Lesogaberan (AZD-3355) HCl is a potent and specific GABAB receptor agonist/activator with EC50 of 8.6 nM for human recombinant GABAB receptor. Affinity (Kis) of Lesogaberan HCl for rat GABAB and GABAA receptors as measured by [3H]GABA binding displacement in meninges: 5.1 nM and 1.4 μM, respectively. Lesogaberan HCl inhibits transient lower esophageal sphincter relaxation via a peripheral mode of action.

Physicochemical Properties

Molecular Formula	C3H9CLFNO2P
Molecular Weight	176.534224271774
Exact Mass	176.004
CAS #	2925644-17-1
Related CAS #	Lesogaberan;344413-67-8;Lesogaberan napadisylate;477956-38-0
PubChem CID	162640398
Appearance	Colorless to light yellow viscous liquid
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	3
Heavy Atom Count	9
Complexity	89.4
Defined Atom Stereocenter Count	1
SMILES	Cl.[P+](C[C@@H](CN)F)(=O)O
InChi Key	CJVIVHIKWIZWOJ-AENDTGMFSA-O
InChi Code	InChI=1S/C3H7FNO2P.ClH/c4-3(1-5)2-8(6)7;/h3H,1-2,5H2;1H/p+1/t3-;/m1./s1
Chemical Name	[(2R)-3-amino-2-fluoropropyl]-hydroxy-oxophosphanium;hydrochloride
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 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)

Biological Activity

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]
ln Vitro	Human islet cell proliferation is enhanced in vitro by leogaberan hydrochloride (3–30 nM)[2].
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].
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.
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.
References	[1]. (R)-(3-amino-2-fluoropropyl) phosphinic acid (AZD3355), a novel GABAB receptor agonist, inhibits transient lower esophageal sphincter relaxation through a peripheral mode of action. J Pharmacol Exp Ther. 2009 Nov;331(2):504-12. [2]. Repurposing Lesogaberan to Promote Human Islet Cell Survival and β-Cell Replication. J Diabetes Res. 2017;2017:6403539.

Solubility Data

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. 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. 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 corn oil and mix evenly. 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.  (Please use freshly prepared in vivo formulations for optimal results.)

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.