Investigation of Curcumin and its Analogs as Adenosine Receptor Agonists for Treating Chronic Pain

Chronic pain debilitates millions of people throughout the world. From the mid‐1990s until the present, the principle pharmacologic treatment for chronic pain has been long‐term administration of opioid medications. However, between 1999 and 2007, the number of deaths related to opioid drug overdose rose throughout the world and more than tripled in the USA, causing concern. In response, studies have been initiated to discover new analgesics that carry a lower risk of addiction and overdose‐related death. All four adenosine receptor (AR) subtypes (A 1 AR, A 2A AR, A 2B AR, A 3 AR) have been investigated as targets for analgesic drugs, but concerns about cardiovascular side effects are impeding translation to the clinic. Drugs that are selective for A 3 AR offer a solution, because they inhibit pain without cardiovascular effects. Our aim is to clarify the structural characteristics of molecules that make them more selective for A 3 AR over other ARs. To generate ARs for testing, three human embryonic kidney cell lines are being grown, expressing A 2A , A 2B , and A 3 ARs respectively. We have selected curcumin as our test molecule because it has documented analgesic properties and because its binding affinity for ARs has not previously been described. We use photochemistry to alter curcumin, changing it from trans‐trans to cis‐trans . Both forms of curcumin are then evaluated for their binding affinity (K i ) for each of the AR subtypes using fluorescent ligand competitive binding assays. Results thus far show that isomerized curcumin binds to ARs more strongly than unmodified curcumin. Further binding assays will reveal whether isomerized curcumin is selective for A 3 AR over other ARs. Further testing with cAMP ELISAs will reveal whether binding of isomerized curcumin is associated with receptor activation. Activation of A 3 AR will result in depressed cAMP levels because A 3 AR is coupled to G α i . Activation of A 2A AR and A 2B AR will result in elevated cAMP levels, because both A 2 ARs are coupled to G α s . In summary, the structure activity relationships discovered by this study will help future pharmacologists to design molecules that target A 3 ARs for the alleviation of chronic pain. Support or Funding Information We thank the Great Plains IDeA CTR program (NIGMS # 1U54GM115458‐01) and the American Chemical Society Petroleum Research Fund (# 54862‐UR4) for their funding support.