Due to their poor metabolic stability and limited blood-brain barrier (BBB) permeability,
endomorphins (EMs) 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 (EM-2)
analogues have been synthesized, which proved to bind with high affinity and selectivity
to the mu-opioid receptors, and showed proteolytic resistance. In this study we have
analyzed the transport characteristics of EM-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
BBB model. The lipohilicity of the analogues, as assessed by their octanol/water partition
coefficients, was higher than that of EM-2. The flux of all four peptides from the
apical (blood) side to the basolateral (brain) side was not saturable in the 10 nM
to 1 mM 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 EM-2, suggesting increased BBB penetration properties. We conclude
that due to their good peptidase resistance and improved transport through brain endothelial
cells these EM-2 analogues will have better analgesic properties in vivo. (c) 2011
John Wiley & Sons A/S.
