November 07, 2013
John Streicher, Ph.D., assistant professor of biomedical sciences, authored an article titled “Development of functionally selective, small molecule agonists at kappa opioid receptors” that was accepted for publication in the Journal of Biological Chemistry.
The article explores a property of the _-Opioid Receptor (KOR) known as “functional selectivity” or “signaling bias,” in which a molecule binding to the receptor can specifically activate one downstream signaling pathway over another.
The KOR is a G protein-coupled receptor (GPCR), and while it has the potential to induce analgesia and helps decrease drug-taking behaviors, KOR activation also has unpleasant side effects. KOR signaling is mediated via G protein pathways and _arrestin pathways, and previous work in the field has suggested that _arrestin2 signaling is responsible for the negative side effects of KOR activation.
In this article, Streicher and his colleagues present their development of two novel chemical classes of KOR agonists that are biased against _arrestin2 signaling and for G protein signaling. These compounds also demonstrate analgesic properties in vivo, much like other KOR agonists.
Future work with these compounds will focus on determining if these drugs produce analgesia without typical KOR negative side effects. This work has the potential to introduce an entirely new class of analgesic drugs without the side effects typical of opioids such as morphine.
The article is scheduled for publication in January and is available as an e-publication.