Effect of guanidino modification and proline substitution on the in vitro stability and blood-brain barrier permeability of endomorphin II

Vincent S. Hau, Jason D. Huber, Christopher R. Campos, Andrzej W. Lipkowski, Aleksandra Misicka, Thomas P Davis

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Endomorphin II (ENDII), an endogenous ligand for the μ-opioid receptor, was investigated as a possible analgesic with fewer side effects than morphine. To improve CNS entry of END II, structural modification was also examined to determine whether Pro4 substitution and cationization affected physico-chemical characteristics, blood-brain barrier (BBB) transport, and analgesic profile. END II and its Pro4-substituted analog, Morphiceptin (MOR), were cationized by guanidino (GU)-addition. MOR was seven times less lipophilic than END II, whereas GU-addition decreased lipophilicity of both peptides. MOR did not affect in vitro BBB permeability; however, GU-addition increased permeability of MOR by 31%. MOR decreased protein binding by 23% compared to END II, whereas GU-addition increased protein binding of both peptides by 71 and 113%, respectively. MOR increased brain t1/2 compared to END II. GU-addition significantly increased t1/2 of MOR and END II in both brain (sixfold and 10-fold, respectively) and serum (over 10-fold). Pro4-substitution and GU-addition enhanced the in vivo analgesia profiles of i.v. administered END II and MOR, but decreased i.c.v. analgesia profiles. This study demonstrates Pro4-substitution decreases protein binding and enhances brain stability while cationization enhances both brain and serum stability with variable effects on BBB permeability. The analgesic profiles show that both Pro4-substitution and cationization enhance i.v. analgesia and thus, are promising structural modifications for the development of successful opioid drugs.

Original languageEnglish (US)
Pages (from-to)2140-2149
Number of pages10
JournalJournal of Pharmaceutical Sciences
Volume91
Issue number10
DOIs
StatePublished - Oct 2002

Fingerprint

Blood-Brain Barrier
Proline
Permeability
Substitution reactions
Brain
Protein Binding
Analgesia
Analgesics
Peptides
morphiceptin
In Vitro Techniques
Opioid Receptors
Serum
Morphine
Opioid Analgesics
Ligands
Pharmaceutical Preparations

Keywords

  • Blood-brain barrier permeability
  • Endomorphin II
  • Guanidino modification
  • In vitro stability
  • Proline substitution

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science

Cite this

Effect of guanidino modification and proline substitution on the in vitro stability and blood-brain barrier permeability of endomorphin II. / Hau, Vincent S.; Huber, Jason D.; Campos, Christopher R.; Lipkowski, Andrzej W.; Misicka, Aleksandra; Davis, Thomas P.

In: Journal of Pharmaceutical Sciences, Vol. 91, No. 10, 10.2002, p. 2140-2149.

Research output: Contribution to journalArticle

Hau, Vincent S. ; Huber, Jason D. ; Campos, Christopher R. ; Lipkowski, Andrzej W. ; Misicka, Aleksandra ; Davis, Thomas P. / Effect of guanidino modification and proline substitution on the in vitro stability and blood-brain barrier permeability of endomorphin II. In: Journal of Pharmaceutical Sciences. 2002 ; Vol. 91, No. 10. pp. 2140-2149.
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