Development of inhibitors of receptor protein tyrosine phosphatase β/ζ (PTPRZ1) as candidates for CNS disorders.
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.
['Pastor|Miryam|M|', 'Fernández-Calle|Rosalía|R|', 'Di Geronimo|Bruno|B|', 'Vicente-Rodríguez|Marta|M|', 'Zapico|José María|JM|', 'Gramage|Esther|E|', 'Coderch|Claire|C|', 'Pérez-García|Carmen|C|', 'Lasek|Amy W|AW|', 'Puchades-Carrasco|Leonor|L|', 'Pineda-Lucena|Antonio|A|', 'de Pascual-Teresa|Beatriz|B|', 'Herradón|Gonzalo|G|', 'Ramos|Ana|A|']
D000818:Animals D000894:Anti-Inflammatory Agents, Non-Steroidal D001812:Blood-Brain Barrier D002352:Carrier Proteins D002460:Cell Line D002470:Cell Survival D002493:Central Nervous System Diseases D016207:Cytokines D004305:Dose-Response Relationship, Drug D004791:Enzyme Inhibitors D006801:Humans D051379:Mice D008958:Models, Molecular D015394:Molecular Structure D051381:Rats D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 D013329:Structure-Activity Relationship
PTPRZ1 CNS disorders Molecular dynamics Drug addiction Synthesis