Transport Characteristics of Endomorphin-2 Analogues in Brain Capillary Endothelial Cells

Jayapal Reddy Mallareddy, Géza Tóth, Csilla Fazakas, Judit Molnár, Péter Nagyoszi, Andrzej W. Lipkowski, István A. Krizbai, Imola Wilhelm

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Because of their poor metabolic stability and limited blood-brain barrier permeability, endomorphins have a low analgesic efficacy when administered systemically. Therefore, it is of great importance to design analogues with improved peptidase resistance and better delivery to the central nervous system. Recently, novel endomorphin-2 analogues have been synthesized, which proved to bind with high affinity and selectivity to the μ-opioid receptors and showed proteolytic resistance. In this study, we have analysed the transport characteristics of endomorphin-2 and three of its analogues [Dmt-Pro-Phe-Phe-NH 2, Tyr-(1S,2R)Acpc-Phe-Phe-NH 2 and Tyr-(1S,2R)Achc-Phe-Phe-NH 2] using an in vitro blood-brain barrier model. The lipophilicity of the analogues, as assessed by their octanol/water partition coefficients, was higher than that of endomorphin-2. The flux of all four peptides from the apical (blood) side to the basolateral (brain) side was not saturable in the 10nm-1mm concentration range, suggesting that a passive mechanism plays a major role in their transport. The permeability coefficient of the analogues was significantly higher than that of endomorphin-2, suggesting increased blood-brain barrier penetration properties. We conclude that because of their good peptidase resistance and improved transport through brain endothelial cells, these endomorphin-2 analogues will have better analgesic properties in vivo.

Original languageEnglish
Pages (from-to)507-513
Number of pages7
JournalChemical Biology and Drug Design
Volume79
Issue number4
DOIs
Publication statusPublished - Apr 1 2012

Keywords

  • Analogues
  • Blood-brain barrier
  • Cerebral endothelial cell
  • Endomorphin
  • Influx
  • Opioid peptides
  • Transport

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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