Novel curcumin analog (cis-trans curcumin) as ligand to adenosine receptors A2A and A2B: potential for therapeutics

Abstract

All four of the adenosine receptor (AR) subtypes mediate pain and have been targeted by pharmacologists to generate new therapeutics for chronic pain. The vanilloid phytochemicals, which include curcumin, capsaicin, and gingerol, have been shown to alleviate pain. However, there is little to no literature on the interaction of vanilloid phytochemicals with ARs. In this study, photochemical methods were used to generate a novel isomer of curcumin (cis-trans curcumin or CTCUR), and the interactions of both curcumin and CTCUR with the two G_s-linked AR subtypes were studied. Competitive binding assays, docking analysis, and confocal fluorescence microscopy were performed to measure binding affinity; cell survival assays were used to measure toxicity; and cAMP assays were performed to measure receptor activation. Competitive binding results indicated that CTCUR binds to both AR A_2A and AR A_2B with K_i values of 5 μM and 7 μM, respectively, which is consistent with our docking results. Fluorescence microscopy data also shows binding for A_2B and A_2A. Cell survival results show that CTCUR and CUR are nontoxic at the tested concentrations in these cell lines. Overall, our results suggest that vanilloid phytochemicals may be slightly modified to increase interaction with G_s-ARs, and thereby can be further explored to provide a novel class of non-opioid antinociceptives.

Keywords: 5'-N-Ethylcarboxamidoadenosine (PubChem CID: 4400); Adenosine; Adenosine receptor A(2A); Adenosine receptor A(2B); Chronic pain; Cis-Trans curcumin (PubChem CID: 969516); Curcumin; Curcumin (PubChem CID: 969516); G(stimulatory).