Inhibition of δ‐Opioid Receptors

Abstract

Opioid addiction and abuse affects between 26 and 36 million people worldwide (Volkow, 2014), prompting researchers to try to design a drug that both has painkilling effects but does not create a dependency. Most opioid analgesics work through activation of mu opioid receptors (MOR). They naturally bind to opioid peptides, such as endomorphins 1 and 2, in order to regulate pain. Another important target is the delta opioid receptor (DOR). Inhibition of DOR has been shown to slow the development of addiction to MOR agonists in animal models of pain. DOR are proteins that transpermeate the cell membrane with seven alpha helices. Schiller and colleagues first reported an endomorphin analogue, DIPP‐NH2, that activates MOR and also inhibits DOR. DIPP‐NH2 is structurally similar to the natural endomorphins, so it can bind DOR through similar mechanisms. The DIPP‐NH2 interacts with the Met132, Tyr129, Val217, Ile277, and Trp284 on DOR. Moreover, one of the two methyl groups on DIPP‐NH2 engages Val281 and Ile277. Finally, a salt bridge forms between the DIPP‐NH2 N‐terminus and Asp128, and this salt bridge is crucial for opioid receptor ligand recognition. The Whitefish Bay High School SMART team (Students Modeling a Research Topic) is modeling DOR using 3D printing technology. DIPP‐NH2 may be the basis of a non‐addictive painkiller, which would be a significant advancement toward alleviating the major societal and financial problem of opioid addiction.Support or Funding InformationThis work was supported by the National Institutes of of Health Science Education Partnership Award (NIH‐SEPA 1R25OD010505‐01) and the National Institutes of Health Clinical and Translational Science Award (NIH‐CTSA UL1RR031973).