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

51 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Pharmaceutical Science

Fingerprint Dive into the research topics of 'Effect of guanidino modification and proline substitution on the in vitro stability and blood-brain barrier permeability of endomorphin II'. Together they form a unique fingerprint.

  • Cite this