Cinnamic Acid Derivatives as Novel Antinociceptives for Acute Pain

Abstract

Search for alternate pain medications has gained more importance in the past few years due to nervous system related side‐effects with opioids, gastrointestinal dysfunction associated with non‐steroidal anti‐inflammatory drugs (NSAIDs), and cardiovascular anomalies with cyclo‐oxygenase‐2 inhibitors (COX‐2). Phytomedicine has been quite effective for treatment of pain, as these have been used for generations in regional communities, and tend to lack any major side‐effects. A dimer of cinnamic acid, Incarvillateine (INCA), derived from the Chinese herb Incarvillea sinensis, has its primary antinociceptive action through the adenosine receptor. Adenosine‐mediated analgesia has become an attractive target as it has the least side‐effects. We hypothesized that derivatives of cinnamic acid dimers, which structurally mimic INCA, show potent antinociceptive action, and their effect is mediated through adenosine receptor action. Compounds were synthesized using novel cavitand‐mediated photodimerization method, which utilizes a macromolecule (gamma‐cyclodextrin) to control the excited state reactivity of photoactive compounds to yield target tetra‐substituted cyclobutanes (dimers). The dimers generated so far show significant suppression of formalin‐induced acute pain in mice hind paw. Antinociceptive effect of ferulic acid dimer and 3‐methoxy cinnamic acid dimer was observed primarily in the inflammatory phase, and the dimer binds to the adenosine 3 receptors (as revealed by computer modeling). The pain suppressing response of these dimers was similar to that observed with indomethacin, an anti‐inflammatory drug. Even though morphine was more effective than the synthesized dimers in reducing neurogenic and inflammatory pain, there was no visible neurogenic side‐effects observed with administration of the dimers as commonly observed with morphine, which suggests a primary non‐opioid action. Our further characterization and selection of INCA analogs, with predominant adenosine receptor action, will help us to generate a new class of antinociceptives with precise chemical modifications using CMP methodology.Support or Funding InformationUNK Undergraduate Research Fellowship (AP, MH, WM, CC); Great Plains IDeA CTR Pilot Grant (MP, SC)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.