Lesogaberan napadisylate

Lesogaberan (AZD-3355) napadisylate is a potent and selective GABAB receptor agonist with an EC50 of 8.6 nM for human recombinant GABAB receptors. Binding affinity (Kis) of 5.1 nM and 1.4 μM for rat brain GABAB and GABAA receptors, respectively[1].

Signaling Pathways >> Membrane Transporter/Ion Channel >> GABA Receptor

Research Areas >> Metabolic Disease

Signaling Pathways >> Neuronal Signaling >> GABA Receptor

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]

Lesogaberan (3-30 nM) enhances human islet cell proliferation in vitro[2]. Cell Proliferation Assay[2] Cell Line: Human islet cells Concentration: 3, 10, and 30 nM Incubation Time: 4 days Result: 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.

Lesogaberan (AZD3355) potently stimulates recombinant human GABAB receptors and inhibits transient lower esophageal sphincter relaxation (TLESR) in dogs, with a biphasic dose-response curve[1]. Oral Lesogaberan (0.08 mg/mL; 48 hours) protects human islet β-cells from apoptosis in islet grafts in mice[2]. Lesogaberan (7 μmol/kg) shows high oral availability (88% in the dog and 100% in the rat) and relatively low systemic clearance in female SpragueDawley rats[1]. Animal Model: Diabetic NOD/scid mice were implanted with human islets[2] Dosage: 0.08 mg/mL Administration: Oral feeding; 48 hours Result: Significantly reduced the percentages of apoptotic islet cells and increased the frequency of insulin+ β-cells in human islet grafts. Animal Model: Female Sprague Dawley rats[1] Dosage: 7 μmol/kg (Pharmacokinetic Analysis) Administration: Oral Result: 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.

[1]. Lehmann A, et al. (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]. Tian J, et al. Repurposing Lesogaberan to Promote Human Islet Cell Survival and β-Cell Replication. J Diabetes Res. 2017;2017:6403539.