Ferulic acid dimer as a non-opioid therapeutic for acute pain

Abstract

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.

Global Research Trends of Herbal Medicine for Pain in Three Decades (1990–2019): A Bibliometric Analysis

“… 18 Another study reports that incarvillateine (INCA), derived from the Chinese herb Incarvillea sinensis , shows potent nonopioid antinociceptive action mediated predominantly through A3AR – adenosine 3 receptor action. 19 …”

Synthesis of esters of diaminotruxillic bis-amino acids by Pd-mediated photocycloaddition of analogs of the Kaede protein chromophore

“…The interest in this type of compound has gained even more relevance in the last few years due to the discovery that truxillic acid derivatives are inhibitors of FABP (fatty acid binding proteins), which are responsible for the cellular reuptake of anandamide, an endocannabinoid neurotransmitter, and that they can be involved in a very efficient treatment for chronic pain [7][8][9][10]. Moreover, alternative mechanisms to explain the antinociception of truxillic compounds have also been reported [11,12] and have generated intense debate. In addition, truxillic derivatives have shown remarkable activity as hepato-protective agents [13] and they also have applications as internal donors in Ziegler-Natta catalysts for polymerization [14] or as building blocks in polymer chemistry [15].…”

Antinociceptive activity of petroleum ether fraction obtained from methanolic extract of Clinacanthus nutans leaves involves the activation of opioid receptors and NO-mediated/cGMP-independent pathway

“…The presence of cinnamic acid in PECN is parallel to the report of Tüzan and Özdemir [46] on the presence of this acid in petroleum ether extract of Galanthus elwesii . Concurrent with this finding, there are reports on the potential of cinnamic acid derivatives [47] to exert antinociceptive activity.…”