title: Halogenation of a capsaicin analogue leads to novel vanilloid TRPV1 receptor antagonists.
abstract: 1. The C-5 halogenation of the vanillyl moiety of resiniferatoxin, an ultrapotent agonist of vanilloid TRPV1 receptors, results in a potent antagonist for these receptors. Here, we have synthesized a series of halogenated derivatives of 'synthetic capsaicin' (nonanoyl vanillamide=nordihydrocapsaicin) differing for the nature (iodine, bromine-chlorine) and the regiochemistry (C-5, C-6) of the halogenation. 2. The activity of these compounds was investigated on recombinant human TRPV1 receptors overexpressed in HEK-293 cells. None of the six compounds exerted any significant agonist activity, as assessed by measuring their effect on TRPV1-mediated calcium mobilization. Instead, all compounds antagonized, to various extents, the effect of capsaicin in this assay. 3. All 6-halo-nordihydrocapsaicins behaved as competitive antagonists against human TRPV1 according to the corresponding Schild's plots, and were more potent than the corresponding 5-halogenated analogues. The iodo-derivatives were more potent than the bromo- and chloro-derivatives. 4. Using human recombinant TRPV1, 6-iodo-nordihydrocapsaicin (IC(50)=10 nM against 100 nM capsaicin) was about four times more potent than the prototypical TRPV1 antagonist, capsazepine, and was tested against capsaicin also on native TRPV1 in: (i) rat dorsal root ganglion neurons in culture; (ii) guinea-pig urinary bladder; and (iii) guinea-pig bronchi. In all cases, except for the guinea-pig bronchi, the compound was significantly more potent than capsazepine as a TRPV1 antagonist. 5. In conclusion, 6-iodo-nordihydrocapsaicin, a stable and easily prepared compound, is a potent TRPV1 antagonist and a convenient replacement for capsazepine in most of the in vitro preparations currently used to assess the activity of putative vanilloid receptor agonists.
authors.affiliation: DiSCAFF, Viale Ferrucci 33, 28100 Novara, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
authors.forename: Selena
authors.initials: S
authors.lastname: Harrison
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.forename: Nives
authors.initials: N
authors.lastname: Daddario
authors.forename: Federica
authors.initials: F
authors.lastname: Bianchi
authors.forename: Aniello
authors.initials: A
authors.lastname: Schiano Moriello
authors.forename: Marcello
authors.initials: M
authors.lastname: Trevisani
authors.forename: Francesca
authors.initials: F
authors.lastname: Benvenuti
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Geppetti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology; D006168:Guinea Pigs; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology / Q000196:embryology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects; D014162:Transfection; D001743:Urinary Bladder / Q000187:drug effects
chemical_list: D006846:Hydrocarbons, Halogenated; D011955:Receptors, Drug; D011994:Recombinant Proteins; D002211:Capsaicin; D002118:Calcium