title: Iodinated N-acylvanillamines: potential "multiple-target" anti-inflammatory agents acting via the inhibition of t-cell activation and antagonism at vanilloid TRPV1 channels.
abstract: Synthetic N-acylvanillamines were designed and developed as metabolically stable compounds with pharmacological potential in analgesia and inflammation because of their interaction with cannabinoid receptors and the vanilloid receptor (TRPV1). Here, we show that arvanil inhibits early events in T-cell receptor (TCR)-mediated T-cell activation, such as calcium mobilization and nuclear factor of activated T-cell activation, and in late events in TCR-mediated activation, such as interleukin (IL)-2 gene transcription, IL-2R expression, and cell-cycle progression. Arvanil also prevents tumor necrosis factor-alpha-induced nuclear factor-kappaB (NF-kappaB) activation by direct inhibition of IkappaBalpha degradation, NF-kappaB binding to DNA, and NF-kappaB-dependent transcription. Aromatic iodination meta to the phenolic hydroxyl (on the 6'-carbon atom) converts arvanil and olvanil from TRPV1 agonists into antagonists. However, this structural modification did not affect the immunosuppressive and proapoptotic activity of these compounds. In summary, we described here novel activities of arvanil on T-cell functions and the development of two novel inhibitors of neurogenic inflammation (6'-I-olvanil and 6'-I-arvanil) endowed with a unique combination of TRPV1 antagonistic-, immunosuppressive-, and NF-kappaB-inhibitory properties. Our findings provide new mechanistic insights into the biological activities of N-alkylvanillamines and should foster the synthesis of improved analogs amenable to pharmaceutical development as analgesic and anti-inflammatory agents.
authors.affiliation: Departamento de Biología Celular, Fisiología e Inmunología, Facultad de Medicina, Universidad de Córdoba, Córdoba, Spain.
authors.forename: Nieves
authors.initials: N
authors.lastname: Márquez
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Caballero
authors.forename: Antonio
authors.initials: A
authors.lastname: Macho
authors.forename: Aniello
authors.initials: A
authors.lastname: Schiano-Moriello
authors.forename: Alberto
authors.initials: A
authors.lastname: Minassi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D007376:Interleukin-2 / Q000235:genetics; D007455:Iodine / Q000737:chemistry*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D010957:Plasmids; D011401:Promoter Regions, Genetic; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors*
chemical_list: D000588:Amines; D007376:Interleukin-2; D016328:NF-kappa B; D050916:TRPV Cation Channels; C121153:arvanil; D007455:Iodine; D002211:Capsaicin