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

Article Details

Citation

Copy to clipboard

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

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

FEBS Lett. 2006 Jan 23;580(2):568-74. Epub 2005 Dec 29.

PubMed ID

16406364 [ View in PubMed

]

Abstract

12-Phenylacetyl-ricinoleoyl-vanillamide (phenylacetylrinvanil, PhAR, IDN5890), is an ultra-potent agonist of human vanilloid TRPV1 receptors also endowed with moderate affinity for human cannabinoid CB(2) receptors. To improve its CB(2) 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 (EC(50) 31-126 nM). Within these compounds, the 12-phenylacetylricinoleyl cyclopropylamide and ethanolamide were the strongest ligands at CB(2) receptors, with K(i) of 22 and 44 nM, and 14- and >20-fold selectivity over cannabinoid CB(1) receptors, respectively. The propyl- and allyl-derivatives also exhibited high affinity at CB(2) receptors (K(i)=40 and 22 nM, with 40 and >80-fold selectivity over CB(1) receptors, respectively), but no activity at TRPV1 receptors. The cyclopropyl- and allyl-derivatives behaved as CB(2) 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 CB(2) or CB(1) receptors. Thus, the manipulation of PhAR led to the development of the first CB(2)/TRPV1 dual ligands and of an entirely new class of inverse agonists at CB(2) receptors. Both types of compounds might find application in the treatment of inflammation, and represent new molecular probes to investigate the endocannabinoid-endovanilloid signalling system.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ricinoleic acid	Cannabinoid receptor 1	Protein	Humans	Unknown	Not Available	Details
Ricinoleic acid	Cannabinoid receptor 2	Protein	Humans	Unknown	Not Available	Details
Ricinoleic acid	Transient receptor potential cation channel subfamily V member 1	Protein	Humans	Unknown	Not Available	Details