A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers

作者：Waldhoer M; Fong J; Jones RM; Lunzer MM; Sharma SK; Kostenis E; Whistler JL^*; Portoghese PS

来源：Proceedings of the National Academy of Sciences, 2005, 102(25): 9050-9055.

DOI：10.1073/pnas.0501112102

• opioid

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.

• 出版日期2005-6-21