Synthesis of resveratrol derivatives as new analgesic drugs through desensitization of the TRPA1 receptor

Syuhei Nakao; Miyuki Mabuchi; Shenglan Wang; Yoko Kogure; Tadashi Shimizu; Koichi Noguchi; Akito Tanaka; Yi Dai

doi:10.1016/j.bmcl.2017.05.025

Synthesis of resveratrol derivatives as new analgesic drugs through desensitization of the TRPA1 receptor

Bioorg Med Chem Lett. 2017 Jul 15;27(14):3167-3172. doi: 10.1016/j.bmcl.2017.05.025. Epub 2017 May 22.

Authors

Syuhei Nakao¹, Miyuki Mabuchi², Shenglan Wang³, Yoko Kogure⁴, Tadashi Shimizu¹, Koichi Noguchi⁵, Akito Tanaka⁶, Yi Dai⁷

Affiliations

¹ Advanced Medical Research Center, Hyogo University of Health Sciences, 1-3-6 Minatojima, Kobe 650-8530, Japan; School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Kobe 650-8530, Japan.
² Advanced Medical Research Center, Hyogo University of Health Sciences, 1-3-6 Minatojima, Kobe 650-8530, Japan.
³ School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Kobe 650-8530, Japan; Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine, Kobe 650-8530, Japan.
⁴ School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Kobe 650-8530, Japan.
⁵ Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
⁶ Advanced Medical Research Center, Hyogo University of Health Sciences, 1-3-6 Minatojima, Kobe 650-8530, Japan; School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Kobe 650-8530, Japan. Electronic address: tanaka-a@huhs.ac.jp.
⁷ School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Kobe 650-8530, Japan; Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine, Kobe 650-8530, Japan; Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan. Electronic address: ydai@huhs.ac.jp.

PMID: 28576617
DOI: 10.1016/j.bmcl.2017.05.025

Abstract

A series of 31 resveratrol derivatives was designed, synthesized and evaluated for activation and inhibition of the TRPA1 channel. Most acted as activators and desensitizers of TRPA1 channels like resveratrol or allyl isothiocyanate (AITC). Compound 4z (HUHS029) exhibited higher inhibitory activity than resveratrol with an IC₅₀ value of 16.1μM. The activity of 4z on TRPA1 was confirmed in TRPA1-expressing HEK293 cells, as well as in rat dorsal root ganglia neurons by a whole cell patch clamp recording. Furthermore, pretreatment with 4z exhibited an analgesic effect on AITC-evoked TRPA1-related pain behavior in vivo.

Keywords: Analgesic drug; HUHS029; Resveratrol; TRPA1.

MeSH terms

Analgesics / chemical synthesis*
Analgesics / pharmacology
Analgesics / therapeutic use
Animals
Calcium Channels / metabolism*
Ganglia, Spinal / drug effects
HEK293 Cells
Humans
Inhibitory Concentration 50
Nerve Tissue Proteins / agonists
Nerve Tissue Proteins / antagonists & inhibitors
Nerve Tissue Proteins / metabolism*
Pain / drug therapy
Patch-Clamp Techniques
Rats
Resveratrol
Stilbenes / chemistry*
TRPA1 Cation Channel
Transient Receptor Potential Channels / agonists
Transient Receptor Potential Channels / antagonists & inhibitors
Transient Receptor Potential Channels / metabolism*

Substances

Analgesics
Calcium Channels
Nerve Tissue Proteins
Stilbenes
TRPA1 Cation Channel
TRPA1 protein, human
Transient Receptor Potential Channels
Resveratrol