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, Victor J Hruby, Thomas P Davis

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

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
JournalPeptides
Volume20
Issue number10
DOIs
StatePublished - Oct 1999

Fingerprint

Halogenation
Blood-Brain Barrier
Permeability
Peptides
Halogens
Pharmaceutical Preparations
Neurology
Central Nervous System
Plasmas
Octanols
Enkephalins
penicillaminyl(2,5)-phenylalanine(6)-enkephalin
Phenylalanine
Opioid Analgesics
Half-Life
Brain
Tissue

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Physiology
  • Cellular and Molecular Neuroscience

Cite this

Gentry, C. L., Egleton, R. D., Gillespie, T., Abbruscato, T. J., Bechowski, H. B., Hruby, V. J., & Davis, T. P. (1999). The effect of halogenation on blood-brain barrier permeability of a novel peptide drug. Peptides, 20(10), 1229-1238. https://doi.org/10.1016/S0196-9781(99)00127-8

The effect of halogenation on blood-brain barrier permeability of a novel peptide drug. / Gentry, C. L.; Egleton, R. D.; Gillespie, T.; Abbruscato, T. J.; Bechowski, H. B.; Hruby, Victor J; Davis, Thomas P.

In: Peptides, Vol. 20, No. 10, 10.1999, p. 1229-1238.

Research output: Contribution to journalArticle

Gentry, CL, Egleton, RD, Gillespie, T, Abbruscato, TJ, Bechowski, HB, Hruby, VJ & Davis, TP 1999, 'The effect of halogenation on blood-brain barrier permeability of a novel peptide drug', Peptides, vol. 20, no. 10, pp. 1229-1238. https://doi.org/10.1016/S0196-9781(99)00127-8
Gentry CL, Egleton RD, Gillespie T, Abbruscato TJ, Bechowski HB, Hruby VJ et al. The effect of halogenation on blood-brain barrier permeability of a novel peptide drug. Peptides. 1999 Oct;20(10):1229-1238. https://doi.org/10.1016/S0196-9781(99)00127-8
Gentry, C. L. ; Egleton, R. D. ; Gillespie, T. ; Abbruscato, T. J. ; Bechowski, H. B. ; Hruby, Victor J ; Davis, Thomas P. / The effect of halogenation on blood-brain barrier permeability of a novel peptide drug. In: Peptides. 1999 ; Vol. 20, No. 10. pp. 1229-1238.
@article{0311b95676aa48889580c41e1e1bd93b,
title = "The effect of halogenation on blood-brain barrier permeability of a novel peptide drug",
abstract = "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.",
keywords = "δ opioid receptor, Blood-brain barrier, Brain endothelial cells, Halogens, Lipophilicity, Peptide drug, Permeability coefficient",
author = "Gentry, {C. L.} and Egleton, {R. D.} and T. Gillespie and Abbruscato, {T. J.} and Bechowski, {H. B.} and Hruby, {Victor J} and Davis, {Thomas P}",
year = "1999",
month = "10",
doi = "10.1016/S0196-9781(99)00127-8",
language = "English (US)",
volume = "20",
pages = "1229--1238",
journal = "Peptides",
issn = "0196-9781",
publisher = "Elsevier Inc.",
number = "10",

}

TY - JOUR

T1 - The effect of halogenation on blood-brain barrier permeability of a novel peptide drug

AU - Gentry, C. L.

AU - Egleton, R. D.

AU - Gillespie, T.

AU - Abbruscato, T. J.

AU - Bechowski, H. B.

AU - Hruby, Victor J

AU - Davis, Thomas P

PY - 1999/10

Y1 - 1999/10

N2 - 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.

AB - 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.

KW - δ opioid receptor

KW - Blood-brain barrier

KW - Brain endothelial cells

KW - Halogens

KW - Lipophilicity

KW - Peptide drug

KW - Permeability coefficient

UR - http://www.scopus.com/inward/record.url?scp=0032759292&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032759292&partnerID=8YFLogxK

U2 - 10.1016/S0196-9781(99)00127-8

DO - 10.1016/S0196-9781(99)00127-8

M3 - Article

C2 - 10573295

AN - SCOPUS:0032759292

VL - 20

SP - 1229

EP - 1238

JO - Peptides

JF - Peptides

SN - 0196-9781

IS - 10

ER -