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

Autor: M. PASTOR, R. FERNANDEZ-CALLE, B. DI GERONIMO, M. VICENTE-RODRIGUEZ, J. ZAPICO, E. GRAMAGE, C. CODERCH, C. PEREZ-GARCIA, A. LASEK, L. PUCHADES-CARRASCO, A. PINEDA-LUCENA, B. DE PASCUAL-TERESA, G. HERRADON, A. RAMOS
Rok vydání: 2018
Předmět:
Zdroj: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe
instname
r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
r-CIPF: Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
Centro de Investigación Principe Felipe (CIPF)
ISSN: 0223-5234
Popis: 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 mu M) 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. (C) 2017 Elsevier Masson SAS. All rights reserved.
Databáze: OpenAIRE
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