Synthesis and biological evaluation of [6]-gingerol analogues as transient receptor potential channel TRPV1 and TRPA1 modulators

• Published in: Bioorganic & medicinal chemistry letters 2012-02, Vol.22 (4), p.1674-1677
• Main Authors: Morera, Enrico, De Petrocellis, Luciano, Morera, Ludovica, Schiano Moriello, Aniello, Nalli, Marianna, Di Marzo, Vincenzo, Ortar, Giorgio
• Format: Article
• Language: English
• Subjects: agonists; antagonists; Biological and medical sciences; Calcium Channels; Catechols - chemical synthesis; Catechols - chemistry; Catechols - pharmacology; Fatty Alcohols - chemical synthesis; Fatty Alcohols - chemistry; Fatty Alcohols - pharmacology; Gingerol analogues; Humans; Inhibitory Concentration 50; Medical sciences; Molecular Structure; Nerve Tissue Proteins - agonists; Nerve Tissue Proteins - antagonists & inhibitors; Pharmacology. Drug treatments; Protein Binding - drug effects; Shogaol analogues; Stereoisomerism; Structure-Activity Relationship; structure-activity relationships; Transient Receptor Potential Channels - agonists; Transient Receptor Potential Channels - antagonists & inhibitors; TRP channels; TRPA1; TRPA1 Cation Channel; TRPV Cation Channels - agonists; TRPV Cation Channels - antagonists & inhibitors; TRPV1
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.12.113

In order to explore the structural determinants for the TRPV1 and TRPA1 agonist properties of gingerols, a series of nineteen analogues (1b–5) of racemic [6]-gingerol (1a) was synthesized and tested on TRPV1 and TRPA1 channels. The exploration of the structure–activity relationships, by modulating the three pharmacophoric regions of [6]-gingerol, led to the identification of some selective TRPV1 agonists/desensitizers of TRPV1 channels (3a, 3f, and 4) and of some full TRPA1 antagonists (2c, 2d, 3b, and 3d).