PurposeSearch for alternate pain medications has gained more importance in the past few years due to adverse effects associated with currently prescribed drugs including nervous system dysfunction with opioids, gastrointestinal discomfort with nonsteroidal anti-inflammatory drugs, and cardiovascular anomalies with cyclooxygenase-2 (COX-2) inhibitors. Phytomedicine has been explored for the treatment of pain, as these have been used for generations in regional communities and tend to lack major side effects in general. One such phytomedicine, incarvillateine (INCA), derived from the Chinese herb Incarvillea sinensis has its primary antinociceptive action through the adenosine receptor, a novel pain target. We hypothesized that derivatives of cinnamic acid dimers, which are structurally similar to INCA, would show potent antinociceptive action and that their effect would be mediated through adenosine receptor action.Materials and methodsDimers of cinnamic acid (INCA analogs) were synthesized using cavitand-mediated photodimerization (CMP) method, which utilizes a macromolecule (γ-cyclodextrin) to control excited state reactivity of photoactive compounds. Acute pain response was assessed by using formalin-induced licking behavior in hind paw of mice, and neurologic function was monitored through locomotor activity, mechanical hyperalgesia, and thermal sensitivity upon administration of test compound. For mechanistic studies, binding to adenosine receptor was determined by using computer modeling.ResultsFerulic acid dimer (FAD), which has the same chemical functionalities on the aromatic ring as INCA, showed significant suppression of formalin-induced acute pain. Antinociceptive effect was observed primarily in the inflammatory phase, and no apparent behavioral changes related to the nervous system were noticeable. Inhibition of opioid receptor did not reverse antinociceptive response, and modeling data suggest adenosine 3 receptor binding.ConclusionFAD (INCA analog) shows potent nonopioid antinociceptive action mediated predominantly through A3AR – adenosine 3 receptor action. Further characterization and selection of such INCA analogs will help us generate a new class of antinociceptives with precise chemical modifications by using CMP methodology.
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.
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