Page 12 - I. Chemical biology and drug discovery

[I. Chemical biology and drug discovery-6]

Development of G protein-biased agonists for human µ-

opioid receptor

In Hee Jang¹˙³˙#, JaeHoon Jung²˙#, Jeong-Hoon Kim¹˙⁴, Sung Goo Park¹˙⁴, Byoung Chul Park¹˙⁴, Sang Kyum Kim³˙*,
Yong-Chul Kim²˙*, Sunhong Kim¹˙⁴˙*

¹Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon

34141, South korea, ²Life sciences, Gwangju Institute of Science and Technology, Gwangju 61005, South korea,
³College of pharmacy, Chungnam national university, Daejeon 34134, South korea, ⁴Bioscience, Korea university of
science and technology, Daejeon 34113, South korea

G-protein-coupling receptor (GPCR) family regulate a variety of physiological processes including inflammation,
muscle movement, and pain. Among them, the μ-opioid receptor is expressed at high levels in the human central

nervous system and gastrointestinal tract, and is known as a main target of morphine. Morphine has been prescribed
as a pain-relieving drug, but unwanted severe side effects have been reported. Some of these side effects are due

to the β-arrestin pathway downstream of the μ-opioid receptor. Researchers have been trying to discover a biased
agonist that activates only G-protein signaling pathway, not β-arrestin signaling pathway, to develop an analgesic

without side effects. As part of this effort, we developed a series of compounds through a structure activity
relationship of PZM21, which is a known biased agonist. Through newly developed assays, we have discovered a

couple of compounds that are biased to Gαi signaling. However, the EC50 of these compounds were higher than
that of PZM21. We are now trying to find a more effective Gαi-biased ligand by performing various analytical

techniques.