The effect of halogenation on blood-brain barrier permeability of a novel peptide drug

C. L. Gentry, R. D. Egleton, T. Gillespie, T. J. Abbruscato, H. B. Bechowski, V. J. Hruby, T. P. Davis

Research output: Contribution to journalArticlepeer-review

113 Scopus citations


The utility of a drug depends on its ability to reach appropriate receptors at the target tissue and remain metabolically stable to produce the desired effect. To improve central nervous system entry of the opioid analgesic [D-Pen2, L-Pen5, Phe6] Enkephalin (DPLPE-Phe), our research group synthesized analogs that had chloro, bromo, fluoro, and iodo halogens on the para positions of the phenylalanine-4 residue. This study reports on investigation of the effect of halogenation on stability, lipophilicity, and in vitro blood-brain barrier permeability of a novel enkephalin analog DPLPE- Phe. The stability of each halogenated DPLPE-Phe analog as well as the amidated and nonamidated parent peptide was tested in plasma and brain. All peptides tested had a half-time disappearance >300 min except for DPLPE-Phe- NH2, which was found to have a half-life of 30 min in plasma. Octanol/saline distribution studies indicated addition of halogens to DPLPE-Phe-OH significantly increased lipophilicity except for p-[F-Phe4]DPLPE-Phe-OH. p- [Cl-Phe4]DPLPE-Phe-OH exhibited the most pronounced increase in lipophilicity. Para-bromo and para-chloro halogen additions significantly enhanced in vitro blood-brain barrier permeability, providing evidence for improved delivery to the central nervous system.

Original languageEnglish (US)
Pages (from-to)1229-1238
Number of pages10
Issue number10
StatePublished - Oct 1999


  • Blood-brain barrier
  • Brain endothelial cells
  • Halogens
  • Lipophilicity
  • Peptide drug
  • Permeability coefficient
  • δ opioid receptor

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Endocrinology
  • Cellular and Molecular Neuroscience


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