Natural prenylated resveratrol analogs arachidin-1 and -3 demonstrate improved glucuronidation profiles and have affinity for cannabinoid receptors

Xenobiotica. 2012 Feb;42(2):139-56. doi: 10.3109/00498254.2011.609570. Epub 2011 Oct 4.


Rationale: The therapeutic promise of trans-resveratrol (tRes) is limited by poor bioavailability following rapid metabolism. We hypothesise that trans-arachidin-1 (tA1) and trans-arachidin-3 (tA3), peanut hairy root-derived isoprenylated analogs of tRes, will exhibit slower metabolism/enhanced bioavailability and retain biological activity via cannabinoid receptor (CBR) binding relative to their non-prenylated parent compounds trans-piceatannol (tPice) and tRes, respectively.

Results: The activities of eight human UDP-glucuronosyltransferases (UGTs) toward these compounds were evaluated. The greatest activity was observed for extrahepatic UGTs 1A10 and 1A7, followed by hepatic UGTs 1A1 and 1A9. Importantly, an additional isoprenyl and/or hydroxyl group in tA1 and tA3 slowed overall glucuronidation. CBR binding studies demonstrated that all analogs bound to CB1Rs with similar affinities (5-18 µM); however, only tA1 and tA3 bound appreciably to CB2Rs. Molecular modelling studies confirmed that the isoprenyl moiety of tA1 and tA3 improved binding affinity to CB2Rs. Finally, although tA3 acted as a competitive CB1R antagonist, tA1 antagonised CB1R agonists by both competitive and non-competitive mechanisms.

Conclusions: Prenylated stilbenoids may be preferable alternatives to tRes due to increased bioavailability via slowed metabolism. Similar structural analogs might be developed as novel CB therapeutics for obesity and/or drug dependency.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding, Competitive
  • Biological Availability
  • CHO Cells
  • Chromatography, High Pressure Liquid
  • Cricetinae
  • Glucuronosyltransferase / chemistry*
  • Hemiterpenes / chemistry
  • Hemiterpenes / pharmacokinetics
  • Hemiterpenes / pharmacology*
  • Humans
  • Kinetics
  • Mass Spectrometry
  • Metabolic Detoxication, Phase II
  • Models, Molecular
  • Prenylation
  • Receptors, Cannabinoid / chemistry*
  • Recombinant Proteins / chemistry
  • Resveratrol
  • Stilbenes / chemistry*
  • Stilbenes / pharmacokinetics
  • Stilbenes / pharmacology*


  • Hemiterpenes
  • Receptors, Cannabinoid
  • Recombinant Proteins
  • Stilbenes
  • arachidin-1
  • arachidin-3
  • Glucuronosyltransferase
  • Resveratrol