Development of inhibitors of receptor protein tyrosine phosphatase β/ζ (PTPRZ1) as candidates for CNS disorders

Eur J Med Chem. 2018 Jan 20:144:318-329. doi: 10.1016/j.ejmech.2017.11.080. Epub 2017 Nov 28.

Abstract

A new series of blood-brain barrier permeable molecules designed to mimic the activity of Pleiotrophin in the CNS has been designed and synthesized. These compounds exert their action by interacting with the intracellular domain PD1 of the Protein Tyrosine-Phosphatase Receptor Z1 (PTPRZ1), and inhibiting its tyrosine phosphatase activity. The most potent compounds 10a and 12b (IC50 = 0,1 μM) significantly increase the phosphorylation of key tyrosine residues of PTPRZ1 substrates involved in neuronal survival and differentiation, and display protective effects against amphetamine-induced toxicity. Docking and molecular dynamics experiments have been used to analyze the binding mode and to explain the observed selectivity against PTP1B. An In vivo experiment has demonstrated that 10a can cross the BBB, thus promoting the possibility of moving forward these candidates for the development of drugs for the treatment of CNS disorders, such as drug addiction and neurodegenerative diseases.

Keywords: CNS disorders; Drug addiction; Molecular dynamics; PTPRZ1; Synthesis.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism
  • Carrier Proteins / chemical synthesis
  • Carrier Proteins / chemistry
  • Carrier Proteins / pharmacology*
  • Cell Line
  • Cell Survival / drug effects
  • Central Nervous System Diseases / drug therapy*
  • Central Nervous System Diseases / metabolism
  • Cytokines / chemical synthesis
  • Cytokines / chemistry
  • Cytokines / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5 / antagonists & inhibitors*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5 / metabolism
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Carrier Proteins
  • Cytokines
  • Enzyme Inhibitors
  • pleiotrophin
  • PTPRZ1 protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5