Inhibition of human equilibrative nucleoside transporters by 4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-6-imino-N-(naphthalen-2-yl)-1,3,5-triazin-2-amine.

Abstract

Equilibrative nucleoside transporters (ENTs) play a crucial role in the transport of nucleoside and nucleoside analogues, which are important for nucleotide synthesis and chemotherapy. In addition, ENTs regulate extracellular adenosine levels in the vicinity of its receptors and hence influence adenosine-related functions. The clinical applications of ENT inhibitors in the treatment of cardiovascular diseases and cancer therapy have been explored in numerous studies. However, all ENT inhibitors to date are selective for ENT1 but not ENT2. In the present study, we investigated the novel compound 4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-6-imino-N-(naphthalen-2-yl)-1,3,5-triazin-2-amine (FPMINT) as an inhibitor of ENT1 and ENT2. Nucleoside transporter-deficient PK15NTD cells stably expressing ENT1 and ENT2 showed that FPMINT inhibited [3H]uridine and [3H]adenosine transport through both ENT1 and ENT2 in a concentration-dependent manner. The IC50 value of FPMINT for ENT2 was 5-10-fold less than for ENT1, and FPMINT could not be displaced with excess washing. Kinetic studies revealed that FPMINT reduced Vmax of [3H]uridine transport in ENT1 and ENT2 without affecting KM. Therefore, we conclude that FPMINT inhibits ENTs in an irreversible and non-competitive manner. Although already selective for ENT2 over ENT1, further modification of the chemical structure of FPMINT may lead to even better ENT2-selective inhibitors of potential clinical, physiological and pharmacological importance.

• Authors: Philip C T Tang, Cui Yang, Rachel Wai-Sum Li, Simon Ming-Yuen Lee, Maggie Pui-Man Hoi, Shun-Wan Chan, Yiu-Wa Kwan, Chung-Ming Tse, George Pak-Heng Leung
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 791 Pg. 544-551 (Nov 15 2016) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 27388143 (Publication Type: Journal Article)
• Copyright: Copyright © 2016. Published by Elsevier B.V.

Chemical References

• 4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-6-imino-N-(naphthalen-2-yl)-1,3,5-triazin-2-amine
• Equilibrative Nucleoside Transporter 1
• Equilibrative-Nucleoside Transporter 2
• Naphthalenes
• Piperazines
• SLC29A1 protein, human
• SLC29A2 protein, human
• Triazines

Topics

• Biological Transport (drug effects)
• Equilibrative Nucleoside Transporter 1 (antagonists & inhibitors, metabolism)
• Equilibrative-Nucleoside Transporter 2 (antagonists & inhibitors, metabolism)
• Gene Expression Regulation (drug effects)
• Humans
• Kinetics
• Naphthalenes (chemistry, pharmacology)
• Piperazines (chemistry, pharmacology)
• Triazines (chemistry, pharmacology)