Pharmacological Characterization of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Inhibitors

  title={Pharmacological Characterization of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Inhibitors},
  author={Amy K. Dickason-Chesterfield and Stephanie R. Kidd and Steven A. Moore and John M. Schaus and Bin Liu and G. Nomikos and Christian C. Felder},
  journal={Cellular and Molecular Neurobiology},
 1. The mechanism of anandamide uptake and disposal has been an issue of considerable debate in the cannabinoid field. Several compounds have been reported to inhibit anandamide uptake or fatty acid amide hydrolase (FAAH; the primary catabolic enzyme of anandamide) activity with varying degrees of potency and selectivity. We recently reported the first evidence of a binding site involved in the uptake of endocannabinoids that is independent from FAAH. There are no direct comparisons of… 
Removal of Endocannabinoids by the Body: Mechanisms and Therapeutic Possibilities
The actions of anandamide and 2-arachidonoylglycerol are terminated by cellular uptake followed by metabolism, and no selective inhibitors of this enzyme are presently available with which to establish the potential of this enzymes as a target for drug development.
Carbamoyl tetrazoles as inhibitors of endocannabinoid inactivation: a critical revisitation.
Overview of the chemical families of fatty acid amide hydrolase and monoacylglycerol lipase inhibitors.
  • S. Vandevoorde
  • Biology, Chemistry
    Current topics in medicinal chemistry
  • 2008
The purpose of this review is to give an overview of the families of synthetic inhibitors of FAAH and MAGL, which contain few members and most of them exhibit a lack of selectivity.
Organized trafficking of anandamide and related lipids.
Identification of intracellular carriers for the endocannabinoid anandamide
Three fatty acid binding proteins (FABPs) known to be expressed in brain were examined as possible intracellular AEA carriers and represent the first proteins known to transport AEA from the plasma membrane to FAAH for inactivation and may therefore be novel pharmacological targets.
Inactivation and Biotransformation of the Endogenous Cannabinoids Anandamide and 2-Arachidonoylglycerol
This review serves as an introduction to the endocannabinoid system with an emphasis on the proteins and events responsible for the termination of AEA and 2-AG signaling.
Inhibition of the cellular uptake of anandamide by genistein and its analogue daidzein in cells with different levels of fatty acid amide hydrolase‐driven uptake
It is investigated whether inhibition of fatty acid amide hydrolase rather than inhibition of endocytosis is the primary determinant of genistein actions upon anandamide uptake.


Role of fatty acid amide hydrolase in the transport of the endogenous cannabinoid anandamide.
Examining anandamide metabolism and uptake in RBL-2H3 cells, which natively express FAAH, as well as wild-type HeLa cells that lack FAAH suggest that FAAH facilitates anandamon uptake but is not solely required for transport to occur.
The endocannabinoid signaling system: Pharmacological and therapeutic aspects
Identification of a high-affinity binding site involved in the transport of endocannabinoids.
Systemic administration of the inhibitor into rodents elevates anandamide levels 5-fold in the brain and demonstrates efficacy in the formalin paw-licking model of persistent pain with no obvious adverse effects on motor function, suggesting that endocannabinoid transporter antagonists may provide a strategy for positive modulation of cannabinoid receptors.
Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172.
The results indicate that anandamideinternalization in mouse brain neurons is independent of FAAH activity, and the compound N-(5Z, 8Z, 11Z, 14Z eicosatetraenyl)-4-hydroxybenzamide (AM1172) blocked [(3)H]anandamide internalization in rodent cortical neurons and human astrocytoma cells without acting as a FAAH substrate or inhibitor.
Design, synthesis, and biological evaluation of new inhibitors of the endocannabinoid uptake: comparison with effects on fatty acid amidohydrolase.
It is hoped that these compounds, particularly the most potent in this series (compound 5, UCM707, with IC(50) values for anandamide uptake and FAAH of 0.8 and 30 microM, respectively), will provide useful tools for the elucidation of the role of the an andamide transporter system in vivo.
Structure—Activity Relationships Among N‐Arachidonylethanolamine (Anandamide) Head Group Analogues for the Anandamide Transporter
The structural requirements for ligandbinding to the CB1 receptor and binding to the transporter are very different; however, the transporter and FAAH share most, but not all, structural requirements.
Anandamide transport.
Accumulation of anandamide: Evidence for cellular diversity