Ferulic Acid Dimer As a Non-Opioid Therapeutic for Acute Pain
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Journal name: Journal of Pain Research Article Designation: ORIGINAL RESEARCH Year: 2018 Volume: 11 Journal of Pain Research Dovepress Running head verso: Priebe et al Running head recto: Ferulic acid dimer as an antinociceptive open access to scientific and medical research DOI: http://dx.doi.org/10.2147/JPR.S161161 Open Access Full Text Article ORIGINAL RESEARCH Ferulic acid dimer as a non-opioid therapeutic for acute pain Alaini Priebe1,* Purpose: Search for alternate pain medications has gained more importance in the past few Megan Hunke1,* years due to adverse effects associated with currently prescribed drugs including nervous system Raquel Tonello2 dysfunction with opioids, gastrointestinal discomfort with nonsteroidal anti-inflammatory drugs, Yogesh Sonawane3 and cardiovascular anomalies with cyclooxygenase-2 (COX-2) inhibitors. Phytomedicine has Temugin Berta2 been explored for the treatment of pain, as these have been used for generations in regional com- munities and tend to lack major side effects in general. One such phytomedicine, incarvillateine Amarnath Natarajan3 (INCA), derived from the Chinese herb Incarvillea sinensis has its primary antinociceptive action Nattamai Bhuvanesh4 through the adenosine receptor, a novel pain target. We hypothesized that derivatives of cinnamic 5 Mahesh Pattabiraman acid dimers, which are structurally similar to INCA, would show potent antinociceptive action 1 Surabhi Chandra and that their effect would be mediated through adenosine receptor action. 1Department of Biology, University Materials and methods: Dimers of cinnamic acid (INCA analogs) were synthesized of Nebraska-Kearney, Kearney, NE, using cavitand-mediated photodimerization (CMP) method, which utilizes a macromolecule USA; 2Department of Anesthesiology, University of Cincinnati, Cincinnati, (γ-cyclodextrin) to control excited state reactivity of photoactive compounds. Acute pain OH, USA; 3Eppley Institute for response was assessed by using formalin-induced licking behavior in hind paw of mice, and Research in Cancer and Allied neurologic function was monitored through locomotor activity, mechanical hyperalgesia, and Diseases, University of Nebraska Medical Center, Omaha, NE, USA; thermal sensitivity upon administration of test compound. For mechanistic studies, binding to 4Department of Chemistry, Texas A&M adenosine receptor was determined by using computer modeling. University, TX, USA; 5Department of Chemistry, University of Nebraska- Results: Ferulic acid dimer (FAD), which has the same chemical functionalities on the aromatic Kearney, Kearney, NE, USA ring as INCA, showed significant suppression of formalin-induced acute pain. Antinociceptive *These authors contributed equally to effect was observed primarily in the inflammatory phase, and no apparent behavioral changes this work related to the nervous system were noticeable. Inhibition of opioid receptor did not reverse antinociceptive response, and modeling data suggest adenosine 3 receptor binding. Conclusion: FAD (INCA analog) shows potent nonopioid antinociceptive action mediated predominantly through A3AR – adenosine 3 receptor action. Further characterization and selec- tion of such INCA analogs will help us generate a new class of antinociceptives with precise chemical modifications by using CMP methodology. Keywords: adenosine, incarvillateine, cinnamic acid, formalin, antinociceptive Introduction Correspondence: Surabhi Chandra Chronic pain is a debilitating condition that affects more people than cancer, diabetes, Department of Biology, University of and heart disease combined. It commonly occurs post-surgery, accompanies several Nebraska-Kearney, 2401 W. 11th Ave, BHS335, Kearney, NE 68849, USA other lingering diseases, and is a leading cause of long-term disability.1 Treatment for Tel +1 308 865 8661 pain has been an ongoing area of research despite a plethora of current medications Fax +1 308 865 8045 Email [email protected] including opioid antagonists, cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal submit your manuscript | www.dovepress.com Journal of Pain Research 2018:11 1075–1085 1075 Dovepress © 2018 Priebe et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work http://dx.doi.org/10.2147/JPR.S161161 you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Priebe et al Dovepress anti-inflammatory drugs (NSAIDs), and to some extent tri- known as photodimerization of alkenes (cinnamic acid [CA] cyclic antidepressants.2 Recently, there is a major emphasis in this case) could afford these compounds in good yields on research for alternate pain medications due to neurological (Figure 2), but the reaction suffers from very poor conver- dysfunction with opioids, gastrointestinal discomfort with sion as the excited state molecules are typically short-lived NSAIDs, and cardiovascular anomalies with COX-2 inhibi- (lifetime: 10–6 s). INCA analogs are known as dimers, as they tors. Several studies emphasize the importance of phyto- are obtained from the combination of two CA monomers. medicine for the treatment of pain, as these have been used Synthetic INCA analogs reported in literature have been for generations in regional communities tested and proven limited to just two stereoisomers: anti head-to-tail (anti H-T) over time and tend to lack major side effects.3,4 and syn head-to-head (syn H-H) of some CAs. A grand total Incarvillateine (INCA) is an active compound from the of <30 compounds (including derivatives) have been investi- Chinese herb, Incarvillea sinensis, which has traditionally gated thus far.5,7,8,12 However, for any one given CA, the four been used to treat rheumatism and relieve pain.5–7 Research stereogenic carbon centers and relative arrangement of the on antinociceptive actions of INCA in chronic and acute pain groups on the cyclobutane core could lead to as many as 11 models indicate that diphenyl-dicarboxylic acid-substituted isomeric structures.13 Thus, there is significant drug discov- cyclobutane core (active core) is essential for its medicinal ery potential if INCA analogs with specific steroisomeric property.7–9 This finding spurred research to synthesize structures could be produced. INCA analogs, which are structural (stereo-/regioisomeric, Our group specializes in the synthesis of these dimers Figure 1) variants of the active core with some additional by including the two CAs within larger molecules with hol- chemical functionalities such as alkyl, hydroxy, alkoxy, and low spaces (cavitands) to increase the chance of encounter halogen groups and study their antinociceptive properties; in excited state. This method known as cavitand-mediated phytocompounds containing this active core are referred to photodimerization (CMP, Figure 3) is effective in producing as truxillic and truxinic acid depending on their structures stereospecific dimers in significant yields.14–16 CMP can thus (Figure 1). produce a wide variety of cinnamic acid dimers (CADs) and Synthesis of INCA analogs by using classical organic is more effective than solid-state photodimerization approach chemistry transformations is inefficient,6,10,11 as it involves used by other groups, which is applicable only to specific multiple synthetic steps, which generate significant waste and reactants.12 As will be discussed below, the syn H-H ferulic reduce overall yield. On the contrary, an excited state reaction acid dimer (FAD) was synthesized in preparative scale by H H CO 3 OH R´ R R´ R OO O O O O R´ R´ R´ R´ H O O O O O OO O N O H H O O R´ R´ R R O R O RRR O N HO H OCH3 Diphenyl dicarboxylic acid unit of INCA: syn H–T syn H–H anti H–H the anti H–T arrangement Incarvillateine An α-truxillic acid An ε-truxillic acid A β-truxinic acid A ζ-truxinic acid Figure 1 Structure of incarvillateine (INCA), the diphenyl dicarboxylic acid core in INCA, its isomeric structural variants, and their corresponding common names (truxillic and truxinic acids). COOH COOH COOH hυ COOH COOH Tail (T) Head Photodimerization COOH COOH HOOC HOOC (H) anti H-H anti H-T trans cinnamic acid syn H-H syn H-T Figure 2 Photodimerization of trans cinnamic acid and the four possible isomeric dimers. 1076 submit your manuscript | www.dovepress.com Journal of Pain Research 2018:11 Dovepress Dovepress Ferulic acid dimer as an antinociceptive COOH γ-CD Photochemical COOH excitation (hυ) syn head-to-head dimer Favorable TT–TT interaction leads to γ-Cyclodextrin syn H–H precursor arrangement γ-CD γ-CD COOR hυ ROOC Unfavorable steric interaction anti head-to-tail dimer favors anti H–T arrangement Figure 3 Cavitand-mediated photodimerization (CMP) method for synthesis of cinnamic acid dimers. using CMP. Other methods involving irradiation of crystals which were further characterized for their pharmacological of ferulic acid obtained from several solvents did not result properties in alleviating pain. From the compounds that we in any dimerization: they were all photo-inert in solid state. have analyzed thus far, syn H-H FAD has been shown to be In search of a new class of antinociceptives,