TY - JOUR
T1 - Interaction of nucleoside analogues with nucleoside transporters in rat brain endothelial cells
AU - Chishty, M
AU - Begley, D J
AU - Abbott, N J
AU - Reichel, A
PY - 2004
Y1 - 2004
N2 - A number of nucleoside analogues, consisting of antiviral compounds and agents designed as adenosine A(1) receptor agonists, were examined for nucleoside transporter affinity using an in vitro model of the blood-brain barrier (BBB), the rat brain endothelial cell line, RBE4. Structure-activity relationships (SAR) were also performed to identify the key structural requirements for transporter recognition and the suitability of these systems for carrier-mediated strategies to deliver therapeutics across the BBB. Adenosine receptor agonists did not show transport affinity for concentrative nucleoside carriers, but exhibited affinity for equilibrative systems (K-i = 10.8-97.9 muM) within the range of K(m)s for natural substrates. However, none of the antiviral compounds tested in this study showed affinity for either class of nucleoside transporter. SAR studies suggest that the hydroxyl group located at the 3'-position of the ribose moiety is an essential requirement for transporter recognition. This may explain the inability of nucleoside derived anti-viral compounds to use these systems despite the significant structural homology with naturally occurring nucleosides. Sites have also been identified which accommodate structural additions with retention of carrier affinity, suggesting that compounds which fail to penetrate the BBB could be attached to these sites for carrier-mediated delivery using a prodrug strategy.
AB - A number of nucleoside analogues, consisting of antiviral compounds and agents designed as adenosine A(1) receptor agonists, were examined for nucleoside transporter affinity using an in vitro model of the blood-brain barrier (BBB), the rat brain endothelial cell line, RBE4. Structure-activity relationships (SAR) were also performed to identify the key structural requirements for transporter recognition and the suitability of these systems for carrier-mediated strategies to deliver therapeutics across the BBB. Adenosine receptor agonists did not show transport affinity for concentrative nucleoside carriers, but exhibited affinity for equilibrative systems (K-i = 10.8-97.9 muM) within the range of K(m)s for natural substrates. However, none of the antiviral compounds tested in this study showed affinity for either class of nucleoside transporter. SAR studies suggest that the hydroxyl group located at the 3'-position of the ribose moiety is an essential requirement for transporter recognition. This may explain the inability of nucleoside derived anti-viral compounds to use these systems despite the significant structural homology with naturally occurring nucleosides. Sites have also been identified which accommodate structural additions with retention of carrier affinity, suggesting that compounds which fail to penetrate the BBB could be attached to these sites for carrier-mediated delivery using a prodrug strategy.
UR - http://www.scopus.com/inward/record.url?scp=4644360379&partnerID=8YFLogxK
U2 - 10.1080/10611860410001731398
DO - 10.1080/10611860410001731398
M3 - Article
VL - 12
SP - 265
EP - 272
JO - Journal of Drug Targeting
JF - Journal of Drug Targeting
IS - 5
ER -