ArticleProceedings of the National Academy of Sciences of the United States of America2005
Identification of a high-affinity binding site involved in the transport of endocannabinoids.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed.
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- LY-2183240 enhances reward-seeking behavior with inducing neuronal excitation and early apoptosis in mouse.iScience · 2024Article
- Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years.Pharmacological reviews · 2023Review
- Endocannabinoids at the synapse and beyond: implications for neuropsychiatric disease pathophysiology and treatment.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2023Review
- Mechanisms of endocannabinoid transport in the brain.British journal of pharmacology · 2022Review
- Untargeted metabolomics identifies the potential role of monocarboxylate transporter 6 (MCT6/SLC16A5) in lipid and amino acid metabolism pathways.Pharmacology research & perspectives · 2022Article
- On the Biomedical Properties of Endocannabinoid Degradation and Reuptake Inhibitors: Pre-clinical and Clinical Evidence.Neurotoxicity research · 2021Review
- The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases.International journal of molecular sciences · 2021Review
- N-Acyl pyrazoles: Effective and tunable inhibitors of serine hydrolases.Bioorganic & medicinal chemistry · 2019Article
- Potential for endocannabinoid system modulation in ocular pain and inflammation: filling the gaps in current pharmacological options.Neuronal signaling · 2018Review
- Neuroprotection in Oxidative Stress-Related Neurodegenerative Diseases: Role of Endocannabinoid System Modulation.Antioxidants & redox signaling · 2018Review
- Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants.Current neuropharmacology · 2015Review
- Discovery libraries targeting the major enzyme classes: the serine hydrolases.Bioorganic & medicinal chemistry letters · 2014Article
- α-Ketoheterocycle inhibitors of fatty acid amide hydrolase: exploration of conformational constraints in the acyl side chain.Bioorganic & medicinal chemistry · 2014Article
- Design, synthesis, and characterization of α-ketoheterocycles that additionally target the cytosolic port Cys269 of fatty acid amide hydrolase.Journal of medicinal chemistry · 2014Article
- AM404 attenuates reinstatement of nicotine seeking induced by nicotine-associated cues and nicotine priming but does not affect nicotine- and food-taking.Journal of psychopharmacology (Oxford, England) · 2013Article
- Chemical probes of endocannabinoid metabolism.Pharmacological reviews · 2013Review
- Marijuana, Spice 'herbal high', and early neural development: implications for rescheduling and legalization.Drug testing and analysis · 2013Review
- Evidence for bidirectional endocannabinoid transport across cell membranes.The Journal of biological chemistry · 2012Article
- Effects of alterations in cannabinoid signaling, alone and in combination with morphine, on pain-elicited and pain-suppressed behavior in mice.The Journal of pharmacology and experimental therapeutics · 2012Article
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12 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Phytocannabinoids, such as the principal bioactive component of marijuana, delta9-tetrahydrocannabinol, have been used for thousands of years for medical and recreational purposes. delta9-Tetrahydrocannabinol and endogenous cannabinoids (e.g., anandamide) initiate their agonist properties by stimulating the cannabinoid family of G protein-coupled receptors (CB1 and CB2). The biosynthesis and physiology of anandamide is well understood, but its mechanism of uptake (resulting in signal termination by fatty acid amide hydrolase) has been elusive. Mounting evidence points to the existence of a specific anandamide transport protein; however, no direct evidence for this protein has been provided. Here, we use a potent, competitive small molecule inhibitor of anandamide uptake (LY2318912, IC50 7.27 +/- 0.510 nM) to identify a high-affinity, saturable anandamide transporter binding site (LY2318912; K(d) = 7.62 +/- 1.18 nM, B(max) = 31.6 +/- 1.80 fmol/mg protein) that is distinct from fatty acid amide hydrolase. 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. Identification of the anandamide transporter binding site resolves a missing mechanistic link in endocannabinoid signaling, and in vivo results suggest that endocannabinoid transporter antagonists may provide a strategy for positive modulation of cannabinoid receptors.
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