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6′‐Guanidinonaltrindole (6′‐GNTI) is a potent and functionally unique kappa opioid agonist that displays bias against beta‐arrestin recruitment and receptor internalization
Author(s) -
Streicher John Michael,
Groer Chad E,
Munro Thomas,
Beguin Cecile,
Cohen Bruce M,
Bohn Laura M
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.626.2
Subject(s) - functional selectivity , internalization , agonist , arrestin , κ opioid receptor , mapk/erk pathway , g protein coupled receptor , pharmacology , partial agonist , chemistry , microbiology and biotechnology , receptor , neuroscience , signal transduction , biology , biochemistry
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.