Unsaturated long-chain N-acyl-vanillyl-amides (N-AVAMs): vanilloid receptor ligands that inhibit anandamide-facilitated transport and bind to CB1 cannabinoid receptors

Biochem Biophys Res Commun. 1999 Aug 19;262(1):275-84. doi: 10.1006/bbrc.1999.1105.


We investigated the effect of changing the length and degree of unsaturation of the fatty acyl chain of N-(3-methoxy-4-hydroxy)-benzyl-cis-9-octadecenoamide (olvanil), a ligand of vanilloid receptors, on its capability to: (i) inhibit anandamide-facilitated transport into cells and enzymatic hydrolysis, (ii) bind to CB1 and CB2 cannabinoid receptors, and (iii) activate the VR1 vanilloid receptor. Potent inhibition of [(14)C]anandamide accumulation into cells was achieved with C20:4 n-6, C18:3 n-6 and n-3, and C18:2 n-6 N-acyl-vanillyl-amides (N-AVAMs). The saturated analogues and Delta(9)-trans-olvanil were inactive. Activity in CB1 binding assays increased when increasing the number of cis-double bonds in a n-6 fatty acyl chain and, in saturated N-AVAMs, was not greatly sensitive to decreasing the chain length. The C20:4 n-6 analogue (arvanil) was a potent inhibitor of anandamide accumulation (IC(50) = 3.6 microM) and was 4-fold more potent than anandamide on CB1 receptors (Ki = 0.25-0.52 microM), whereas the C18:3 n-3 N-AVAM was more selective than arvanil for the uptake (IC(50) = 8.0 microM) vs CB1 receptors (Ki = 3.4 microM). None of the compounds efficiently inhibited [(14)C]anandamide hydrolysis or bound to CB2 receptors. All N-AVAMs activated the cation currents coupled to VR1 receptors overexpressed in Xenopus oocytes. In a simple, intact cell model of both vanilloid- and anandamide-like activity, i.e., the inhibition of human breast cancer cell (HBCC) proliferation, arvanil was shown to behave as a "hybrid" activator of cannabinoid and vanilloid receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Amidohydrolases / metabolism
  • Animals
  • Arachidonic Acids / antagonists & inhibitors*
  • Arachidonic Acids / chemistry
  • Arachidonic Acids / metabolism
  • Binding Sites
  • Biological Transport / drug effects
  • Capsaicin / analogs & derivatives*
  • Capsaicin / chemistry
  • Capsaicin / metabolism
  • Capsaicin / pharmacology
  • Cell Division / drug effects
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / enzymology
  • Cell Membrane / metabolism
  • Diffusion / drug effects
  • Electric Conductivity
  • Endocannabinoids
  • Fatty Acids, Unsaturated / chemistry
  • Fatty Acids, Unsaturated / metabolism*
  • Fatty Acids, Unsaturated / pharmacology
  • Humans
  • Ligands
  • Mice
  • Oocytes / drug effects
  • Oocytes / metabolism
  • Polyunsaturated Alkamides
  • Rats
  • Receptor, Cannabinoid, CB2*
  • Receptors, Cannabinoid
  • Receptors, Drug / agonists
  • Receptors, Drug / genetics
  • Receptors, Drug / metabolism*
  • Xenopus laevis


  • Arachidonic Acids
  • Cnr2 protein, rat
  • Endocannabinoids
  • Fatty Acids, Unsaturated
  • Ligands
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB2
  • Receptors, Cannabinoid
  • Receptors, Drug
  • arvanil
  • olvanil
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • Capsaicin
  • anandamide