Transport Characteristics of Endomorphin-2 Analogues in Brain Capillary Endothelial Cells.

Mallareddy, JR [Mallareddy, Jayapelreddy (biokémia), szerző] Biokémiai Intézet (SZBK); Toth, G [Tóth, Géza (Radiokémia), szerző] Biokémiai Intézet (SZBK); Fazakas, C [Fazakas, Csilla (biofizika), szerző] Biofizikai Intézet (SZBK); Molnar, J [Molnár, Judit (biofizika), szerző] Biofizikai Intézet (SZBK); Nagyoszi, P [Nagyőszi, Péter (biofizika), szerző] Biofizikai Intézet (SZBK); Lipkowski, AW; Krizbai, IA [Krizbai, István Adorján (Neurobiológia), szerző] Biofizikai Intézet (SZBK); Wilhelm, I ✉ [Wilhelm, Imola Mária (Neurobiológia), szerző] Biofizikai Intézet (SZBK)

Angol nyelvű Szakcikk (Folyóiratcikk) Tudományos
Megjelent: CHEMICAL BIOLOGY & DRUG DESIGN 1747-0277 1747-0285 79 (4) pp. 507-513 2012
  • SJR Scopus - Biochemistry: Q2
  • Általános orvostudomány
  • Biológiai tudományok
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.
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2023-06-08 13:55