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- Title
Transport Characteristics of Endomorphin-2 Analogues in Brain Capillary Endothelial Cells.
- Authors
Mallareddy, Jayapal Reddy; Tóth, Géza; Fazakas, Csilla; Molnár, Judit; Nagyőszi, Péter; Lipkowski, Andrzej W.; Krizbai, István A.; Wilhelm, Imola
- 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-NH2, Tyr-(1 S,2 R)Acpc-Phe-Phe-NH2 and Tyr-(1 S,2 R)Achc-Phe-Phe-NH2] 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 10 n m-1 m m 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.
- Subjects
PERMEABILITY; ANALGESICS; PEPTIDASE; PROTEOLYTIC enzymes; OPIOID receptors; DRUG lipophilicity
- Publication
Chemical Biology & Drug Design, 2012, Vol 79, Issue 4, p507
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/j.1747-0285.2011.01306.x