First "hybrid" ligands of vanilloid TRPV1 and cannabinoid CB2 receptors and non-polyunsaturated fatty acid-derived CB2-selective ligands

G Appendino, M G Cascio, S Bacchiega, A S Moriello, A Minassi, A Thomas, R Ross, R Pertwee, L De Petrocellis, V Di Marzo

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12-Phenylacetyl-ricinoleoyl-vanillamide (phenylace-tylrinvanil, PhAR, IDN5890), is an ultra-potent agonist of human vanilloid TRPV1 receptors also endowed with moderate affinity for human cannabinoid CB2 receptors. To improve its CB2 affinity and temper its potency at TRPV1, the modification of the polar headgroup and the lipophilic 12-acylgroup of PhAR was pursued. Replacement of the vanillyl headgroup of PhAR with various aromatic or alkyl amino groups decreased activity at TRPV1 receptors, although the dopamine, cyclopropylamine, 1'-(R)- and 1'-(S)-methyl-ethanolamine, and ethanolamine derivatives retained significant potency (EC50 31-126 nM). Within these compounds, the 12-phenylacetylricinoleyl cyclopropylamide and ethanolamide were the strongest ligands at CB2 receptors, with K-i of 22 and 44 nM, and 14- and > 20-fold selectivity over cannabinoid CB1 receptors, respectively. The propyl- and allyl-derivatives also exhibited high affinity at CB2 receptors (K-i = 40 and 22 nM, with 40 and > 80-fold selectivity over CB1 receptors, respectively), but no activity at TRPV1 receptors. The cyclopropyl- and allyl-derivatives behaved as CB2 inverse agonists in the GTP-gamma-S binding assay. Addition of para-methoxy, -tert-butyl or -chlorine groups to the 12-phenylacetyl moiety of PhAR produced compounds that retained full potency at TRPV1 receptors, but with improved selectivity over CB2 or CB1 receptors. Thus, the manipulation of PhAR led to the development of the first CB2/TRPV1 dual ligands and of an entirely new class of inverse agonists at CB2 receptors. Both types of compounds might find application in the treatment of inflammation, and represent new molecular probes to investigate the endo-cannabinoid-endovanilloid signalling system. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)568-574
Number of pages7
JournalFEBS Letters
Publication statusPublished - 2006


  • endocannabinoid
  • vanilloid
  • inflammation
  • receptor
  • channel
  • anandamide

Cite this

Appendino, G., Cascio, M. G., Bacchiega, S., Moriello, A. S., Minassi, A., Thomas, A., Ross, R., Pertwee, R., De Petrocellis, L., & Di Marzo, V. (2006). First "hybrid" ligands of vanilloid TRPV1 and cannabinoid CB2 receptors and non-polyunsaturated fatty acid-derived CB2-selective ligands. FEBS Letters, 580, 568-574.