6′‐Guanidinonaltrindole (6′‐GNTI) is a potent and functionally unique kappa opioid agonist that displays bias against beta‐arrestin recruitment and receptor internalization
Year: 2011
Type: article
Abstract: Functional selectivity is a phenomenon whereby different ligands activate distinct signaling cascades through the same receptor. Functional selectivity may offer a means to target desired aspects of the receptor signaling response while avoiding unwanted side effects. The kappa opioid receptor (KOR) is a widely expressed G-protein coupled receptor that is involved in modulating reward, mood, sexual behavior and other brain functions. We report here that the KOR agonist 6′-guanidinonaltrindole (6′-GNTI) is a functionally selective, potent agonist at the KOR. 6′-GNTI activates G-protein coupling and ERK MAPK and alters whole cell impedance in KOR expressing cells as a partial (G-protein coupling) or full (ERK, impedance) agonist with a greater potency than the standard KOR agonist U69,593. In contrast, 6′-GNTI weakly induces beta-arrestin2 recruitment to the KOR, and is unable to induce KOR internalization. Furthermore, 6′-GNTI acts as a partial (G-protein coupling, ERK) or full (beta-arrestin recruitment, internalization) antagonist against U69,593 activity in these assays. These unique features of 6′-GNTI make the drug a useful tool for dissecting functionally selective signaling pathways at the KOR both in vitro and in vivo, and may also provide a useful scaffold for developing functionally selective KOR ligands for clinical treatment of KOR related disorders, such as dysphoria in drug addiction.
Source: The FASEB Journal
Institutions: Scripps Research Institute, Harvard University, McLean Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1456701676