title: First "hybrid" ligands of vanilloid TRPV1 and cannabinoid CB2 receptors and non-polyunsaturated fatty acid-derived CB2-selective ligands.
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.
authors.affiliation: Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Via Bovio 6, 28100 Novara, Italy. Giovanni.appendino@pharm.unipmn.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cascio
authors.forename: Sara
authors.initials: S
authors.lastname: Bacchiega
authors.forename: Aniello Schiano
authors.initials: AS
authors.lastname: Moriello
authors.forename: Alberto
authors.initials: A
authors.lastname: Minassi
authors.forename: Adèle
authors.initials: A
authors.lastname: Thomas
authors.forename: Ruth
authors.initials: R
authors.lastname: Ross
authors.forename: Roger
authors.initials: R
authors.lastname: Pertwee
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000577:Amides / Q000737:chemistry / Q000378:metabolism; D000588:Amines / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D002460:Cell Line; D063388:Endocannabinoids; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D000577:Amides; D000588:Amines; D001095:Arachidonic Acids; D063388:Endocannabinoids; D005227:Fatty Acids; D008024:Ligands; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C078814:anandamide