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

Maria Waldhoer, Jamie Fong, Robert M. Jones, Mary M. Lunzer, Shiv K. Sharma, Evi Kostenis, Philip S. Portoghese, Jennifer Whistler

Research output: Contribution to journalArticlepeer-review

293 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)9050-9055
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number25
StatePublished - Jun 21 2005
Externally publishedYes


  • Opioid

ASJC Scopus subject areas

  • General


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