Received for publication October 11, 2005.
Revised December 31, 2005.
Accepted for publication January 3, 2006.

Iodinated N-acylvanillamines. Potential "Multiple-Target" Anti-inflammatory Agents Acting Via 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 due to their interaction with cannabinoid receptors (CBs) and the vanilloid receptor (TRPV1). Here we show that Arvanil, but not Olvanil, inhibits early events in T cell receptor (TCR)-mediated T-cell activation such as calcium mobilization and NF-B activation, as well as late events in TCR-mediated activation like IL-2 gene transcription, IL-2R expression and cell cycle progression. Arvanil also prevents tumor necrosis factor- (TNF)-induced NF-B activation by direct inhibition of IB)- degradation, NF-B binding to DNA, and NF-B 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 pro-apoptotic activity of these compounds. In summary, we have 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-B inhibitory properties. Our findings provide new mechanistic insights into the biological activities of N-alkylvanillamines and should foster the synthesis of improved analogues amenable to pharmaceutical development as analgesic and anti-inflammatory agents.

Key words: Cannabinoid, Capsaicin/vanilloid, NFkappaB, Structure/function/mechanism