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A Personal Retrospective: Elevating Anandamide (AEA) By Targeting Fatty Acid Amide Hydrolase (FAAH) And The Fatty Acid Binding Proteins (FABPs)
Published 2016 · Chemistry, Medicine
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This perspective was adapted from a Career Achievement Award talk given at the International Cannabinoid Research Society Symposium in Bukovina, Poland on June 27, 2016. As a biochemist working in the neurosciences, I was always fascinated with neurotransmitter inactivation. In 1993 we identified an enzyme activity that breaks down anandamide. We called the enzyme anandamide amidase, now called FAAH. We and other laboratories developed FAAH inhibitors that were useful reagents that also proved to have beneficial physiological effects and until recently, new generations of inhibitors were in clinical trials. Nearly all neurotransmitters are water soluble and as such, require a transmembrane protein transporter to pass through the lipid membrane for inactivation inside the cell. However, using model systems, we and others have shown that this is unnecessary for anandamide, an uncharged hydrophobic molecule that readily diffuses across the cellular membrane. Interestingly, its uptake is driven by the concentration gradient resulting from its breakdown mainly by FAAH localized in the endoplasmic reticulum. We identified the FABPs as intracellular carriers that “solubilize” anandamide, transporting anandamide to FAAH. Compounds that bind to FABPs block AEA breakdown, raising its level. The cannabinoids (THC and CBD) also were discovered to bind FABPs and this may be one of the mechanisms by which CBD works in childhood epilepsy, raising anandamide levels. Targeting FABPs may be advantageous since they have some tissue specificity and do not require reactive serine hydrolase inhibitors, as does FAAH, with potential for off-target reactions. At the International Cannabis Research Society Symposium in 1992, Raphe Mechoulam revealed that his laboratory isolated an endogenous lipid molecule that binds to the CB1 receptor (cannabinoid receptor type 1) and this became the milestone paper published in December of that year describing anandamide (AEA, Devane et al., 1992). As to be expected, this discovery raised the issues of AEA's synthesis and breakdown.
This paper references
New players in the fatty acyl ethanolamide metabolism.
Iffat Ara Sonia Rahman (2014)
The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs—A practical view
C. Fowler (2015)
The Cellular Uptake of Anandamide Is Coupled to Its Breakdown by Fatty-acid Amide Hydrolase*
D. Deutsch (2001)
The putative endocannabinoid transport blocker LY2183240 is a potent inhibitor of FAAH and several other brain serine hydrolases.
J. Alexander (2006)
Fatty Acid Binding Protein-1 (FABP1) and the Human FABP1 T94A Variant: Roles in the Endocannabinoid System and Dyslipidemias
F. Schroeder (2016)
Chemical and mutagenic investigations of fatty acid amide hydrolase: evidence for a family of serine hydrolases with distinct catalytic properties.
M. Patricelli (1999)
Structural Adaptations in a Membrane Enzyme That Terminates Endocannabinoid Signaling
M. Bracey (2002)
Evidence against the presence
Trifluoromethyl ketone inhibitors of fatty acid amide hydrolase: a probe of structural and conformational features contributing to inhibition.
D. Boger (1999)
The Insertion and Transport of Anandamide in Synthetic Lipid Membranes Are Both Cholesterol-Dependent
E. Di Pasquale (2009)
Identification of intracellular carriers for the endocannabinoid anandamide
M. Kaczocha (2009)
An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee
J. P. Huggins (2012)
Enzymatic synthesis and degradation
Anandamide Uptake (1993)
This is an Open Access article distribut...
Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides
B. Cravatt (1996)
New report on drug trial disaster in France
B. Casassus (2016)
A catalytically silent FAAH-1 variant drives anandamide transport in neurons
J. Fu (2012)
Fatty acid sulfonyl fluorides inhibit anandamide metabolism and bind to the cannabinoid receptor.
D. Deutsch (1997)
Effect of phenylmethylsulphonyl fluoride on the potency of anandamide as an inhibitor of electrically evoked contractions in two isolated tissue preparations.
R. Pertwee (1995)
The movement of N
C. J. Hillard (2000)
Enzymatic formation of N-acylethanolamines from N-acylethanolamine plasmalogen through N-acylphosphatidylethanolamine-hydrolyzing phospholipase D-dependent and -independent pathways.
K. Tsuboi (2011)
Characterization of mice lacking candidate N-acyl ethanolamine biosynthetic enzymes provides evidence for multiple pathways that contribute to endocannabinoid production in vivo.
G. Simon (2010)
Endocannabinoid transport revisited.
S. Nicolussi (2015)
Carrier-mediated uptake of the endogenous cannabinoid anandamide in RBL-2H3 cells.
F. Rakhshan (2000)
Structure-guided inhibitor design for human FAAH by interspecies active site conversion
Mauro Mileni (2008)
Enzymatic synthesis of anandamide, an endogenous ligand for the cannabinoid receptor, by brain membranes.
W. Devane (1994)
Molecular Targets of Cannabidiol in Neurological Disorders
Clementino Ibeas Bih (2015)
Inhibitors of anandamide breakdown.
D. Deutsch (1997)
Fatty Acid Binding Protein-1 (FABP1) and the Human FABP1
Inhibitory properties of ibuprofen and its amide analogues towards the hydrolysis and cyclooxygenation of the endocannabinoid anandamide
C. Fowler (2013)
Role of fatty acid amide hydrolase in the transport of the endogenous cannabinoid anandamide.
T. Day (2001)
Anandamide transport: a critical review.
S. Glaser (2005)
M. J. McFarland (2004)
Endocannabinoid transport revisited. Vitam
S. 89108 Nicolussi (2015)
Identification of two serine
R. L. Omeir (1999)
Tanezumab takes on pain due to osteoarthritis of the knee
Effects of anandamide
S. R. Childers (1994)
Enzymatic synthesis of anandamide
W. A. Devane (1994)
Carriermediated uptake of the endogenous cannabinoid anandamide in RBL-2H3 cells
F Rakhshan (2000)
Endocannabinoid tone versus constitutive activity of cannabinoid receptors
A. Howlett (2011)
Fatty acid amide hydrolase inhibitors: a patent review (2009 – 2014)
A. Lodola (2015)
Fatty acid amide hydrolase inhibitors--progress and potential.
I. Khanna (2011)
The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review.
C. Fowler (2015)
Unique pathway for anandamide synthesis
A. A. Izzo (2011)
Discovering potent and selective reversible inhibitors of enzymes in complex proteomes
D. Leung (2003)
Lipidomics profile of a NAPE-PLD KO mouse provides evidence of a broader role of this enzyme in lipid metabolism in the brain.
E. Leishman (2016)
Enhancement of the behavioral effects of endogenous and exogenous cannabinoid agonists by phenylmethyl sulfonyl fluoride
R. Vann (2012)
Multiple pathways involved in the biosynthesis of anandamide
J. Liu (2008)
Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets
M. Furuhashi (2008)
Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice.
S. Nicolussi (2014)
Role of fatty acid
T. A. Day (2001)
Anandamide transport: a critical review The movement of Narachidonoylethanolamine (anandamide) across cellular membranes
S T Glaser (2000)
Novel inhibitors of brain, neuronal, and basophilic anandamide amidohydrolase.
L. De Petrocellis (1997)
Structure and function of fatty acid amide hydrolase.
M. K. McKinney (2005)
Structure and Function.
H. Kowarzyk (1910)
Accumulation of anandamide: Evidence for cellular diversity
C. Hillard (2005)
Effect of an unstirred layer on the membrane permeability of anandamide Published, JLR Papers in Press, December 19, 2005.
I. Bojesen (2006)
Formation and inactivation of endogenous cannabinoid anandamide in central neurons
V. Marzo (1994)
Arachidonoyl ethanolamide - as a substrate for anandamide amidase
R. L. Omeir (1995)
Endocannabinoid tone versus constitutive activity
D. G. Deutsch (2011)
Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172.
D. Fegley (2004)
Microsomal synthesis of fatty acid amides.
N. Bachur (1966)
Transport of endocannabinoids across the plasma membrane and within the cell
C. Fowler (2013)
Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB1) receptors in the regenerating liver
B. Mukhopadhyay (2011)
Role of FAAH-Like Anandamide Transporter in Anandamide Inactivation
KwanNok Leung (2013)
Anandamide externally added to lipid vesicles containing trapped fatty acid amide hydrolase (FAAH) is readily hydrolyzed in a sterol-modulated fashion.
M. Kaczocha (2012)
V. DiMarzo (1946)
The cloned rat hydrolytic enzyme responsible for the breakdown of anandamide also catalyzes its formation via the condensation of arachidonic acid and ethanolamine
G. Arreaza (1997)
Effects of anandamide on cannabinoid receptors in rat brain membranes.
S. Childers (1994)
Selective inhibition of anandamide cellular uptake versus enzymatic hydrolysis--a difficult issue to handle.
C. Fowler (2004)
Evidence against the presence of an anandamide transporter
S. Glaser (2003)
Involvement of Fatty Acid Amide Hydrolase and Fatty Acid Binding Protein 5 in the Uptake of Anandamide by Cell Lines with Different Levels of Fatty Acid Amide Hydrolase Expression: A Pharmacological Study
E. Björklund (2014)
Isolation and structure of a brain constituent that binds to the cannabinoid receptor.
W. Devane (1992)
Ibuprofen inhibits rat brain
G. Tiger (1997)
Arachidonoyl ethanolamide-[1,2-14C] as a substrate for anandamide amidase.
R. Omeir (1995)
Metabolism of N-acylethanolamine phospholipids by a mammalian phosphodiesterase of the phospholipase D type.
P. Schmid (1983)
Unique pathway for anandamide synthesis and liver regeneration
A. Izzo (2011)
The fatty acid amide hydrolase (FAAH).
D. Deutsch (2002)
Chemical and mutagenic
M. P. Patricelli (1999)
Characterization of mice
G. M. Simon (2010)
Fatty acid amide hydrolase inhibitors
C. W. Alexander (2011)
Exploiting Nanotechnologies and TRPV1 Channels to Investigate the Putative Anandamide Membrane Transporter
A. Ligresti (2010)
Fatty acid amide hydrolase
A. Lodola (2015)
Fatty acid amide hydrolase inhibitors: a patent review
A Lodola (2009)
Exploiting nanotechnologies and TRPV1
Has FLAT fallen flat?
C. Fowler (2014)
Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
F. Leweke (2012)
Fatty Acid-binding Proteins (FABPs) Are Intracellular Carriers for Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD)*
Matthew W. Elmes (2015)
Methyl arachidonyl fluorophosphonate: a potent irreversible inhibitor of anandamide amidase.
D. Deutsch (1997)
Targeting Fatty Acid Binding Protein (FABP) Anandamide Transporters – A Novel Strategy for Development of Anti-Inflammatory and Anti-Nociceptive Drugs
William T. Berger (2012)
Properties of rat liver N-acylethanolamine amidohydrolase.
P. Schmid (1985)
Ibuprofen inhibits rat brain deamidation of anandamide at pharmacologically relevant concentrations. Mode of inhibition and structure-activity relationship.
C. Fowler (1997)
Crystallographic study of FABP5 as an intracellular endocannabinoid transporter.
B. Sanson (2014)
Fatty Acid-binding Proteins Transport N-Acylethanolamines to Nuclear Receptors and Are Targets of Endocannabinoid Transport Inhibitors*
M. Kaczocha (2011)
N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: a novel enzyme of the beta-lactamase fold family releasing anandamide and other N-acylethanolamines.
N. Ueda (2005)
Inhibitors of arachidonoyl ethanolamide hydrolysis.
B. Koutek (1994)
Identification of two serine residues involved in catalysis by fatty acid amide hydrolase.
R. Omeir (1999)
The movement of N-arachidonoylethanolamine (anandamide) across cellular membranes.
C. Hillard (2000)
Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist.
D. Deutsch (1993)
Oxygenated metabolites of anandamide and 2-arachidonoylglycerol: conformational analysis and interaction with cannabinoid receptors, membrane transporter, and fatty acid amide hydrolase.
M. van der Stelt (2002)
Membrane transport of anandamide through resealed human red blood cell membranes Published, JLR Papers in Press, June 1, 2005. DOI 10.1194/jlr.M400498-JLR200
I. Bojesen (2005)
Cannabinoid properties of methylfluorophosphonate analogs.
B. Martin (2000)
Membrane transport of anandamide
I. N. Bojesen (2005)
Oxygenated metabolites of anandamide
This paper is referenced by
Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders
E. Galaj (2019)
Sterol Carrier Protein-2/Sterol Carrier Protein-x/Fatty Acid Binding Protein-1 Ablation Impacts Response of Brain Endocannabinoid to High-Fat Diet.
G. Martin (2019)
Cannabinoide in der Schmerzmedizin
M. Karst (2018)
N-stearoyltyrosine protects primary cortical neurons against oxygen-glucose deprivation-induced apoptosis through inhibiting anandamide inactivation system
Heng-Jing Cui (2017)
Cannabidiol Does Not Dampen Responses to Emotional Stimuli in Healthy Adults
D. Arndt (2017)
Therapeutic Prospects of Cannabidiol for Alcohol Use Disorder and Alcohol-Related Damages on the Liver and the Brain
J. De Ternay (2019)
Xie2-64, a novel CB2 receptor inverse agonist, reduces cocaine abuse-related behaviors in rodents
C. Jordan (2020)
Endocannabinoid System: An Update
N. Battista (2017)
Targeting the endocannabinoid system as a potential anticancer approach
Rico Schwarz (2018)
The Cannabis Conundrum: Look Both Ways before Crossing a Deserted Road.
Theodore J. Witek (2019)
Distinctive Evidence Involved in the Role of Endocannabinoid Signalling in Parkinson’s Disease: A Perspective on Associated Therapeutic Interventions
T. Behl (2020)
REGULATING HYDROLASES OF THE ENDOCANNABINOID SYSTEM: NOVEL PHOTOMETRIC ASSAYS FOR DRUG DISCOVERY
M. Miceli (2018)
SAR studies on truxillic acid mono esters as a new class of antinociceptive agents targeting fatty acid binding proteins.
S. Yan (2018)
Impact of Fabp1 Gene Ablation on Uptake and Degradation of Endocannabinoids in Mouse Hepatocytes.
A. McIntosh (2018)
miRNA expression profiles and molecular networks in resting and LPS-activated BV-2 microglia—Effect of cannabinoids
A. Juknat (2019)
Opioid‐sparing effects of cannabinoids on morphine analgesia: participation of CB1 and CB2 receptors
Xiaohong Chen (2019)
Enhanced endocannabinoid tone as a potential target of pharmacotherapy
M. Toczek (2018)
Two fatty acid‐binding proteins expressed in the intestine interact differently with endocannabinoids
May Poh Lai (2020)
Distinct functions of endogenous cannabinoid system in alcohol abuse disorders
B. S. Basavarajappa (2019)
Heritability and family-based GWAS analyses of the N-acyl ethanolamine and ceramide plasma lipidome
K. McGurk (2020)
Molecular mechanism with regard to the binding selectivity of inhibitors toward FABP5 and FABP7 explored by multiple short molecular dynamics simulations and free energy analyses.
Jianzhong Chen (2020)
The endocannabinoid signaling pathway as an emerging target in pharmacotherapy, earmarking mitigation of destructive events in rheumatoid arthritis.
Ishnoor Kaur (2020)
Cannabinoids and the Microbiota-Gut-Brain-Axis: Emerging Effects of Cannabidiol and Potential Applications to Alcohol Use Disorders.
Hollis C Karoly (2019)
Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years
M. Maccarrone (2017)
Lipidomics: A Corrective Lens for Enzyme Myopia.
H. Bradshaw (2017)
Cannabidiol attenuates the rewarding effects of cocaine in rats by CB2, 5-TH1A and TRPV1 receptor mechanisms
E. Galaj (2019)
The Antinociceptive Agent SBFI-26 Binds to Anandamide Transporters FABP5 and FABP7 at Two Different Sites.
Hao-Chi Hsu (2017)
A perspective review on fatty acid amide hydrolase (FAAH) inhibitors as potential therapeutic agents.
R. K. P. Tripathi (2019)
Mammalian enzymes responsible for the biosynthesis of N-acylethanolamines.
Z. Hussain (2017)