Design, synthesis, and biological evaluation of new inhibitors of the endocannabinoid uptake:: Comparison with effects on fatty acid amidohydrolase

A new series of arachidonic acid derivatives were synthesized and evaluated as inhibitors of the endocannabinoid uptake. Most of them are able to inhibit anandamide uptake with IC50 values in the low micromolar range IC50 = 0.8-24 muM). In general, the compounds had only weak effects upon Cbeta(1), Cbeta(2), and VR1 receptors (K-i > 1000-10000 nM). In addition, there was no obvious relationship between the abilities of the compounds to affect anandamide uptake and to inhibit anandamide metabolism by fatty acid amidohydrolase (FAAH; IC50 = 30-113 muM). This indicates that the compounds do not exert their effects secondarily to FAAH inhibition. It is hoped that these compounds, particularly the most potent in this series (compound 5, UCM707, with IC50 values for anandamide uptake and FAAH of 0.8 and 30 muM, respectively), will provide useful tools for the elucidation of the role of the anandamide transporter system in vivo.