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

Abstract

1. 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.

2. 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.

3. 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.

Keywords::

• UDP-glucuronosyltransferases
• molecular modelling
• natural products
• G-protein activity
• bioproduction
• cannabinoid receptors

Acknowledgments

The authors would like to thank Anna Dineva for her technical assistance in carrying out the screening experiments with the UGT2B isoforms. FMB was supported by the Arkansas Biosciences Institute, National Science Foundation-EPSCoR (grant # EPS− 0701890; Center for Plant-Powered Production-P3), Arkansas ASSET Initiative and the Arkansas Science and Technology Authority. RJD was supported by USA National Institutes of Health (NIH) Grant Number 5P20RR021929 from the National Center for Research Resources (NCRR) and his research group’s investigations were conducted in a facility constructed with support from research facilities improvement program C06 RR-14503-01 from the NIH NCRR. AR-P was supported by USA National Institutes of Health (NIH) Grant Number GM075893 from the National Institute of General Medical Sciences (NIGMS).

Declaration of interest

AR-P and RJD were supported by USA National Institutes of Health (NIH) Grant Numbers GM075893 from the National Institute of General Medical Sciences (NIGMS) and 5P20RR021929, respectively, from the National Center for Research Resources (NCRR). RJD and his research group’s investigations were conducted in a facility constructed with support from research facilities improvement program C06 RR-14503-01 from the NIH NCRR. The content in this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of NIH, NIGMS or NCRR.