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Cited by 356Cannabis and Cannabinoid ResearchIon Channels and ReceptorsPain Mechanisms and Treatments

Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin‐like activity

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De Petrocellis, Luciano, Bisogno, Tiziana, Davis, John B, Pertwee, Roger G, Di Marzo, Vincenzo·2000·FEBS Letters
DOI 10.1016/s0014-5793(00)02082-2
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Abstract

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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Crossref · 10.1016/s0014-5793(00)02082-2

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  • Pain and thermoregulatory pathways contain both TRPV1 and CB1 receptors.

    “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]

    The Introduction reports that VR1 (TRPV1) and CB1 occur in some of the same brain regions, including the hypothalamus, and that VR1 occurs in dorsal root sensory neurons. It does not establish that both receptors are present in pain and thermoregulatory pathways specifically. Page numbers were not available in our copy. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • AM404 is an agonist at TRPV1 receptors and inhibits cellular anandamide uptake, increasing endogenous cannabinoid levels.

    “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]

    The Abstract (page unavailable) reports that AM404 activates VR1/TRPV1 and inhibits cellular anandamide transport. The Introduction describes anandamide uptake as part of the process that terminates its activity, but the paper does not show that AM404 increases endogenous cannabinoid levels. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • At pain-relieving doses, AM404 generated in rat brain areas rich in FAAH can activate CB1 receptors indirectly and TRPV1 receptors directly.

    “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]

    The Results and discussion (page not available) show that AM404 inhibits anandamide uptake and directly activates the human VR1 receptor, now called TRPV1. The Introduction explains that anandamide is a CB1 agonist, which is consistent with an indirect CB1 mechanism. The paper does not establish that paracetamol produces AM404 in FAAH-rich rat brain regions, or that these receptor effects occur at analgesic doses. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • At roughly 10 nM, AM404 activates rat and human TRPV1, whereas meaningful COX-1/COX-2 inhibition and prostaglandin E2 reduction need micromolar levels.

    “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]

    The Results and discussion section reports that AM404 potently activates human VR1, supporting the human-receptor part of the claim. The passages do not establish activation of rat VR1 at roughly 10 nM, and a search of our copy found no COX-1, COX-2, or prostaglandin E2 result to support the micromolar comparison. Page numbers were not available in the indexed passages. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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Cites

Flagged first, then by citations

Research works printed but not linked: 9

  1. Ueda, N., Pu¡enbarger, R.A., Yamamoto, S. and Deutsch, D. (2000) Chem. Phys. Lipids, in press.
  2. Di Marzo, V., Breivogel, C., Bisogno, T., Melck, D., Patrick, G., Tao, Q., Szallasi, A., Razdan, R.K. and Martin, B.R. (2000) Eur. J. Pharmacol., in press.
  3. Jerman, J.C., Brough, S.J., Davis, J.B., Middlemiss, D.N. and Smart, D. (2000) Br. J. Pharmacol. (Proc. Suppl.) 129, 73P.
  4. Hayes, P., Meadows, H.J., Gunthorpe, M.J., Harries, M.H. et al. (2000) Pain, in press.
  5. Herkenham, M., Lynn, A.B., Little, M.D., Johnson, M.R., Mel- vin, L.S., de Costa, B.R. and Rice, K.C. (1990) Proc. Natl. Acad. Sci. USA 87, 1932^1936.
  6. Mezey, E., Toth, Z.E., Cortright, D.N., Arzubi, M.K., Krause, J.E., Elde, R., Guo, A., Blumberg, P.M. and Szallasi, A. (2000) Proc. Natl. Acad. Sci. USA 97, 3655^3660.
  7. Bisogno, T., Melck, D., Bobrov, Y., De Petrocellis, L., Gret- skaya, N.M., Bezuglov, V.V. and Di Marzo, V. (2000) Biochem. J., in press.
  8. Jarai, Z., Wagner, J.A., Varga, K., Lake, K.D., Compton, D.R., Martin, B.R., Zimmer, A.M., Bonner, T.I., Buckley, N.E., Me- zey, E., Razdan, R.K., Zimmer, A. and Kunos, G. (1999) Proc. Natl. Acad. Sci. USA 96, 14136^14141.
  9. De Petrocellis, L., Melck, D., Palmisano, A., Bisogno, T., Laez- za, C., Bifulco, M. and Di Marzo, V. (1998) Proc. Natl. Acad. Sci. USA 95, 8375^8380.

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Authors
De Petrocellis, L., Bisogno, T., Davis, J. B., Pertwee, R. G., & Di Marzo, V.
Affiliations
  • National Research Council (IT)
  • University of Aberdeen (GB)
ORCID
Venue
FEBS Letters
Publisher
Wiley
Published
2000-10-09
Volume
483
Issue
1
Pages
52-56
ISSN
  • 0014-5793 (ISSN-L)
  • 1873-3468
DOI
10.1016/s0014-5793(00)02082-2
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
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • FEBS Letters (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Health Sciences › Medicine › Physiology › 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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