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

Abstract

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.

• Authors: Zhaohong Qin, Nihar R Pandey, Xun Zhou, Chloe A Stewart, Aswin Hari, Hua Huang, Alexandre F R Stewart, Jean Michel Brunel, Hsiao-Huei Chen
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 458 Issue 1 Pg. 21-7 (Feb 27 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 25623533 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• 3-N-1(spermine)-7, 24-dihydroxy-5-cholestane 24-sulfate
• Cholestanes
• Enzyme Inhibitors
• Insulin
• claramine
• Spermine
• Receptor, Insulin
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Protein Tyrosine Phosphatase, Non-Receptor Type 2
• Ptpn1 protein, mouse
• Ptpn2 protein, mouse

Topics

• Animals
• Cells, Cultured (drug effects)
• Cholestanes (chemical synthesis, chemistry, pharmacology)
• Diabetes Mellitus, Experimental (drug therapy, metabolism)
• Eating (drug effects)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Insulin (metabolism, pharmacology)
• Male
• Mice
• Mice, Mutant Strains
• Neurons (drug effects, metabolism)
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (antagonists & inhibitors, metabolism)
• Protein Tyrosine Phosphatase, Non-Receptor Type 2 (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, Insulin (metabolism)
• Spermine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Weight Loss (drug effects)