6'-Guanidinonaltrindole (6'-GNTI) is a potent and functionally unique kappa opioid agonist that displays bias against beta-arrestin recruitment and receptor internalization

<p>Endogenous ligands, and drugs which mimic their effects, can activate multiple second messenger pathways through one receptor. Structurally distinct ligands can bias G protein coupled receptor (GPCR) signaling towards selected cellular signaling pathways both in cell culture and in vivo. The implications of such signaling divergence is particularly intriguing considering that engaging differential pathways may be useful for imparting different and distinct pharmacological effects in vivo. The kappa opioid receptor (KOR) can be activated in just such a manner to induce differential signaling. In this study, we find that 6'-guanidinonaltrindole (6’-GNTI) is a partial agonist at KOR in regards to G protein coupling while it is a full agonist at the receptor for activating ERK and for its ability to induce changes in cellular impedance. In all three signaling assays, 6’-GNTI is more potent than the standard selective kappa opioid agonist, U69,593. Interestingly, 6’-GNTI does not promote βarrestin-2 recruitment and receptor internalization and therefore displays bias against this signaling pathway. Moreover, 6’-GNTI partially antagonizes U69,593-stimulated G protein coupling and fully blocks U69,593-stimulated βarrestin2 coupling and KOR internalization. 6’-GNTI also displays functional selectivity in vivo by acting as an inverse agonist for G protein coupling in spinal cord but not striatum, and by differentially activating ERK MAPK and Akt in primary neonatal striatal neurons. Thus, 6’-GNTI is a unique ligand of the KOR that may prove useful in delineating functionally selective signaling complexes and behaviors both in vitro and in vivo.</p> <p>Presented on 10th April 2011 at Experimental Biology (Washington DC).</p> <p>Abstract published as:</p> <p>Streicher JM, Groer CE, Munro T, Béguin C, Cohen BM, Bohn LM (2011): 6'-Guanidinonaltrindole (6'-GNTI) is a potent and functionally unique kappa opioid agonist that displays bias against beta-arrestin recruitment and receptor internalization.<br>The FASEB Journal, 25(Meeting Abstracts):626.2.</p> <p>Full report subsequently published as:</p> <p>Schmid CL, Streicher JM, Groer CE, Munro TA, Zhou L, Bohn LM (2013): Functional Selectivity of 6′-Guanidinonaltrindole (6′-GNTI) at κ-Opioid Receptors in Striatal Neurons.<br>Journal of Biological Chemistry, 288(31):22387-22398. doi:10.1074/jbc.M113.476234<br>© the American Society for Biochemistry and Molecular Biology.</p