Design and synthesis of TRPV1 antagonists: probing the D-Region binding site using Amidoalkyl substituents

Abstract

Transient receptor potential vanilloid subfamily 1 (TRPV1) is a membrane bound ion channel that mediates the pain response elicited by capsaicin, resiniferatoxin, and similar drugs. Structure activity studies of compounds that bind to TRPV1 indicate several binding sites, namely: 1) an aromatic ?A? region, 2) a polar ?B? region, and 3) a hydrophobic ?C? region. A fourth region has recently been proposed based on the structure of resiniferatoxin. This ?D? region is thought to be responsible for the increased potency of the drug. A new series of potential TRPV1 antagonists was designed incorporating molecular features intended to interact with the known A, B, and C binding sites. In order to investigate the interaction of the D binding region, amidoalkyl groups were incorporated into the target structures. The synthesis of several members of the target series was accomplished using a convergent synthetic strategy. Ultimately these compounds will be tested for their effectiveness as TRPV1 antagonists.