enkephalin--ala(2)-mephe(4)-gly(5)- and 6--guanidinonaltrindole

There has been much speculation regarding the functional relevance of G protein-coupled receptor heterodimers, primarily because demonstrating their existence in vivo has proven to be a considerable challenge. Here we show that the opioid agonist ligand 6'-guanidinonaltrindole (6'-GNTI) has the unique property of selectively activating only opioid receptor heterodimers but not homomers. Importantly, 6'-GNTI is an analgesic, thereby demonstrating that opioid receptor heterodimers are indeed functionally relevant in vivo. However, 6'-GNTI induces analgesia only when it is administered in the spinal cord but not in the brain, suggesting that the organization of heterodimers is tissue-specific. This study demonstrates a proof of concept for tissue-selective drug targeting based on G protein-coupled receptor heterodimerization. Importantly, targeting opioid heterodimers could provide an approach toward the design of analgesic drugs with reduced side effects.

Topics: Analgesics; Cell Line; Dimerization; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Guanidines; Humans; Kidney; Kinetics; Naltrexone; Receptors, G-Protein-Coupled; Receptors, Opioid; Transfection