title: Unsaturated long-chain N-acyl-vanillyl-amides (N-AVAMs): vanilloid receptor ligands that inhibit anandamide-facilitated transport and bind to CB1 cannabinoid receptors.
abstract: We investigated the effect of changing the length and degree of unsaturation of the fatty acyl chain of N-(3-methoxy-4-hydroxy)-benzyl-cis-9-octadecenoamide (olvanil), a ligand of vanilloid receptors, on its capability to: (i) inhibit anandamide-facilitated transport into cells and enzymatic hydrolysis, (ii) bind to CB1 and CB2 cannabinoid receptors, and (iii) activate the VR1 vanilloid receptor. Potent inhibition of [(14)C]anandamide accumulation into cells was achieved with C20:4 n-6, C18:3 n-6 and n-3, and C18:2 n-6 N-acyl-vanillyl-amides (N-AVAMs). The saturated analogues and Delta(9)-trans-olvanil were inactive. Activity in CB1 binding assays increased when increasing the number of cis-double bonds in a n-6 fatty acyl chain and, in saturated N-AVAMs, was not greatly sensitive to decreasing the chain length. The C20:4 n-6 analogue (arvanil) was a potent inhibitor of anandamide accumulation (IC(50) = 3.6 microM) and was 4-fold more potent than anandamide on CB1 receptors (Ki = 0.25-0.52 microM), whereas the C18:3 n-3 N-AVAM was more selective than arvanil for the uptake (IC(50) = 8.0 microM) vs CB1 receptors (Ki = 3.4 microM). None of the compounds efficiently inhibited [(14)C]anandamide hydrolysis or bound to CB2 receptors. All N-AVAMs activated the cation currents coupled to VR1 receptors overexpressed in Xenopus oocytes. In a simple, intact cell model of both vanilloid- and anandamide-like activity, i.e., the inhibition of human breast cancer cell (HBCC) proliferation, arvanil was shown to behave as a "hybrid" activator of cannabinoid and vanilloid receptors.
authors.affiliation: Istituto per la Chimica di Molecole di Interesse Biologico, Università di Napoli Federico II, 80131, Napoli, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Melck
authors.forename: T
authors.initials: T
authors.lastname: Bisogno
authors.forename: L
authors.initials: L
authors.lastname: De Petrocellis
authors.forename: H
authors.initials: H
authors.lastname: Chuang
authors.forename: D
authors.initials: D
authors.lastname: Julius
authors.forename: M
authors.initials: M
authors.lastname: Bifulco
authors.forename: V
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004058:Diffusion / Q000187:drug effects; D004553:Electric Conductivity; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D051379:Mice; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D051381:Rats; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D002211:Capsaicin; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated; D008024:Ligands; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000099252:Fatty Acid Amide Hydrolases; C469526:Cnr2 protein, rat; C121153:arvanil; C054256:olvanil; C078814:anandamide