title: Transport characteristics of endomorphin-2 analogues in brain capillary endothelial cells.
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-NH(2) , Tyr-(1S,2R)Acpc-Phe-Phe-NH(2) and Tyr-(1S,2R)Achc-Phe-Phe-NH(2) ] 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 10nm-1mm 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.
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Jayapal Reddy
authors.initials: JR
authors.lastname: Mallareddy
authors.forename: Géza
authors.initials: G
authors.lastname: Tóth
authors.forename: Csilla
authors.initials: C
authors.lastname: Fazakas
authors.forename: Judit
authors.initials: J
authors.lastname: Molnár
authors.forename: Péter
authors.initials: P
authors.lastname: Nagyőszi
authors.forename: Andrzej W
authors.initials: AW
authors.lastname: Lipkowski
authors.forename: István A
authors.initials: IA
authors.lastname: Krizbai
authors.forename: Imola
authors.initials: I
authors.lastname: Wilhelm
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry* / Q000493:pharmacokinetics*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000098:blood supply*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics*; D010539:Permeability; D051381:Rats
chemical_list: D000701:Analgesics, Opioid; D009842:Oligopeptides; C105294:endomorphin 2