Three-Dimensional Quantitative Structure−Activity Relationships and Activity Predictions of Human TRPV1 Channel Antagonists:  Comparative Molecular Field Analysis and Comparative Molecular Similarity Index Analysis of Cinnamides

Abstract

3D-QSAR models for human TRPV1 channel antagonists were developed based on comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA), using a training set of 61 cinnamide TRPV1 antagonists and tested on an independent test set of 47 antagonists. Molecular alignment procedure included weights for both internal energy and atom-to-atom matching against a reference or probe. Sensitivity of results on partial charge assignments was explored using multiple charge sets. AM1-BCC charge assignments gave better results for both CoMFA and CoMSIA models. For the best CoMFA model, the statistics are, r2 = 0.96, q2 = 0.58, n = 61 for the training set and r2 = 0.50, n = 47 for the test set. For the best CoMSIA model, the statistics are r2 = 0.95, q2 = 0.57, n = 61 for the training set and r2 = 0.48, n = 47 for the test set. These models are consistent with the proposed binding modes and interactions of known activators of the TRPV1 channel such as capsaicin, in a structural model of the TM3/4 helical region of TRPV1.

Mizoroki–Heck Reactions with 4‐Phenoldiazonium Salts

“…This substrate was chosen because the products resulting from a Mizoroki-Heck reaction, the cinnamic amides 8, have recently attracted some attention as antagonists of certain ion channels. [55,56] Similar to substrate 5, the reaction fails completely with the methoxy-substituted diazonium salts 1a and 1d, whereas yields of 91% and 88%, respectively, were achieved with phenoldiazonium salts 1c and 1e (Table 4).…”

Medicinal chemistry of the vanilloid (Capsaicin) TRPV1 receptor: current knowledge and future perspectives

“…3D-QSAR models (CoMFA and CoMSIA) developed for the aryl cinnamides predict binding modes which are consistent with the previously developed models. It is predicted that these molecules also bind in the TM3/4 region of the TRPV1 channel [Vishwanadhan et al, 2007].…”

Intrathecal [6]‐Gingerol Administration Alleviates Peripherally induced Neuropathic Pain in Male Sprague–Dawley Rats

“…[6]‐Gingerol [(S)‐5‐hydroxy‐1‐(4‐hydroxy‐3‐methoxyphenyl)‐3‐decanone] is one of the major pungent components of ginger ( Zingiber officinale ), a plant commonly used as a spice in a variety of food preparations and beverages, and as a drug in traditional Chinese medicine (Grzanna et al ., ). [6]‐Gingerol is a structural analog of capsaicin, and recent molecular modeling studies indicate that the vanillyl moiety, as well as the long unsaturated acyl chain, have significant impacts on relative binding affinities with the TRPV1 receptor (Viswanadhan et al ., ). Consequently, the chemical structure similarities of [6]‐gingerol with capsaicin suggest that it could be a good ligand of the TRPV1 receptor and potentially be used to treat neuropathic and chronic pain.…”