title: Natural prenylated resveratrol analogs arachidin-1 and -3 demonstrate improved glucuronidation profiles and have affinity for cannabinoid receptors.
abstract: BACKGROUND
  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.
authors.affiliation: Arkansas Biosciences Institute, Arkansas State University, AR, USA.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Brents
authors.forename: Fabricio
authors.initials: F
authors.lastname: Medina-Bolivar
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Seely
authors.forename: Vipin
authors.initials: V
authors.lastname: Nair
authors.forename: Stacie M
authors.initials: SM
authors.lastname: Bratton
authors.forename: Luis
authors.initials: L
authors.lastname: Nopo-Olazabal
authors.forename: Ronak Y
authors.initials: RY
authors.lastname: Patel
authors.forename: Haining
authors.initials: H
authors.lastname: Liu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Doerksen
authors.forename: Paul L
authors.initials: PL
authors.lastname: Prather
authors.forename: Anna
authors.initials: A
authors.lastname: Radominska-Pandya
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D014453:Glucuronosyltransferase / Q000737:chemistry*; D045782:Hemiterpenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D013058:Mass Spectrometry; D050217:Metabolic Detoxication, Phase II; D008958:Models, Molecular; D054876:Prenylation; D043882:Receptors, Cannabinoid / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D045782:Hemiterpenes; D043882:Receptors, Cannabinoid; D011994:Recombinant Proteins; D013267:Stilbenes; C520888:arachidin-1; C553171:arachidin-3; D014453:Glucuronosyltransferase; D000077185:Resveratrol