Functional properties of Claramine: A novel PTP1B inhibitor and insulin-mimetic compound

• Published in: Biochemical and biophysical research communications Vol. 458; no. 1; pp. 21 - 27
• Main Authors: Qin, Zhaohong, Pandey, Nihar R., Zhou, Xun, Stewart, Chloe A., Hari, Aswin, Huang, Hua, Stewart, Alexandre F.R., Brunel, Jean Michel, Chen, Hsiao-Huei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.02.2015
• Subjects: Animals; Body weight; Cells, Cultured - drug effects; Cholestanes - chemical synthesis; Cholestanes - chemistry; Cholestanes - pharmacology; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Eating - drug effects; Energy expenditure; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Food intake; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Insulin - metabolism; Insulin - pharmacology; Male; Mice; Mice, Mutant Strains; Neurons - drug effects; Neurons - metabolism; Protein tyrosine phosphatase; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Insulin - metabolism; Spermine - analogs & derivatives; Spermine - chemical synthesis; Spermine - chemistry; Spermine - pharmacology; Trodusquemine; Type 2 diabetes; Weight Loss - drug effects; Type 2 diabetes; Energy expenditure; Trodusquemine; Protein tyrosine phosphatase; Food intake; Body weight
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2015.01.040

Protein tyrosine phosphatase 1B (PTP1B) inhibits insulin signaling, interfering with its control of glucose homeostasis and metabolism. PTP1B activity is elevated in obesity and type 2 diabetes and is a major cause of insulin resistance. Trodusquemine (MSI-1436) is a “first-in-class” highly selective inhibitor of PTP1B that can cross the blood–brain barrier to suppress feeding and promote insulin sensitivity and glycemic control. Trodusquemine is a naturally occurring cholestane that can be purified from the liver of the dogfish shark, Squalus acanthias, but it can also be manufactured synthetically by a fairly laborious process that requires several weeks. Here, we tested a novel easily and rapidly (2 days) synthesized polyaminosteroid derivative (Claramine) containing a spermino group similar to Trodusquemine for its ability to inhibit PTP1B. Like Trodusquemine, Claramine displayed selective inhibition of PTP1B but not its closest related phosphatase TC-PTP. In cultured neuronal cells, Claramine and Trodusquemine both activated key components of insulin signaling, with increased phosphorylation of insulin receptor-β (IRβ), Akt and GSK3β. Intraperitoneal administration of Claramine or Trodusquemine effectively restored glycemic control in diabetic mice as determined by glucose and insulin tolerance tests. A single intraperitoneal dose of Claramine, like an equivalent dose of Trodusquemine, suppressed feeding and caused weight loss without increasing energy expenditure. In summary, Claramine is an alternative more easily manufactured compound for the treatment of type II diabetes. •Elevated PTP1B activity underlies insulin resistance in type 2 diabetes.•Trodusquemine is a selective inhibitor of PTP1B but is difficult to synthesize.•Claramine is a Trodusquemine-related compound that is easily synthesized.•Claramine is a novel selective inhibitor of PTP1B.•Claramine restores glycemic control in diabetic mice.