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Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin‐like activity
Open accessAbstract
Some synthetic agonists of the VR1 vanilloid (capsaicin) receptor also inhibit the facilitated transport into cells of the endogenous cannabinoid anandamide (arachidonoylethanolamide, AEA). Here we tested several AEA derivatives containing various derivatized phenyl groups or different alkyl chains as either inhibitors of the AEA membrane transporter (AMT) in intact cells or functional agonists of the VR1 vanilloid receptor in HEK cells transfected with the human VR1. We found that four known AMT inhibitors, AM404, arvanil, olvanil and linvanil, activate VR1 receptors at concentrations 400–10 000‐fold lower than those necessary to inhibit the AMT. However, we also found three novel AEA derivatives, named VDM11, VDM12 and VDM13, which inhibit the AMT as potently as AM404 but exhibit little or no agonist activity at hVR1. These compounds are weak inhibitors of AEA enzymatic hydrolysis and poor CB 1/CB 2 receptor ligands. We show for the first time that, despite the overlap between the chemical moieties of AMT inhibitors and VR1 agonists, selective inhibitors of AEA uptake that do not activate VR1 (e.g. VDM11) can be developed.
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“TRPV1 (and also cannabinoid CB 1 ) receptors are present in pain and thermoregulatory pathways (66,111,165,209,210,216).”
From Paracetamol: New Vistas of an Old Drug (2006) · cites this paper as [66]
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“N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids”
From Paracetamol: New Vistas of an Old Drug (2006) · cites this paper as [66]
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“At analgesic doses of paracetamol, AM404 that is formed in rat brain regions expressing high levels of FAAH, can indirectly activate CB 1 receptors and directly activate TRPV1 receptors (66,102,235).”
From Paracetamol: New Vistas of an Old Drug (2006) · cites this paper as [66]
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“At this concentration AM404 activates both rat (102,235) and human (66) TRPV1 receptors, while significant COX-1 and COX-2 inhibition and prostaglandin E 2 formation reduction are obtained at micromolar concentrations (102).”
From Paracetamol: New Vistas of an Old Drug (2006) · cites this paper as [66]
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Metadata
- Authors
- De Petrocellis, L., Bisogno, T., Davis, J. B., Pertwee, R. G., & Di Marzo, V.
- Affiliations
- National Research Council (IT)
- University of Aberdeen (GB)
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 2000-10-09
- Volume
- 483
- Issue
- 1
- Pages
- 52-56
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- OpenAlex
- W2005828463
- Cited by
- 347
- References
- 33
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 6 · 2017: 10 · 2016: 5 · 2015: 11 · 2014: 7 · 2013: 14 · 2012: 14
- FWCI
- 15.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- FEBS Letters (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Keywords
- capsaicin receptor, AM404, olvanil, receptor selectivity, cannabinoid signaling
- MeSH terms
- Animals, Arachidonic Acids, Binding, Competitive, Biological Transport, Calcium, Capsaicin, Cell Line, Dose-Response Relationship, Drug, Humans, Ligands, Receptors, Drug, Tumor Cells, Cultured, Receptors, Cannabinoid, TRPV Cation Channels, Rats, Polyunsaturated Alkamides, Endocannabinoids
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