A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers.
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.
Waldhoer
Maria
M
Ernest Gallo Clinic and Research Center, University of California, San Francisco, CA 94608, USA.
Fong
Jamie
J
Jones
Robert M
RM
Lunzer
Mary M
MM
Sharma
Shiv K
SK
Kostenis
Evi
E
Portoghese
Philip S
PS
Whistler
Jennifer L
JL
D000700:Analgesics / Q000494:pharmacology*; D002460:Cell Line; D019281:Dimerization; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007668:Kidney; D007700:Kinetics; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000187:drug effects / Q000378:metabolism*; D011957:Receptors, Opioid / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014162:Transfection
C503316:6'-guanidinonaltrindole; D000700:Analgesics; D006146:Guanidines; D043562:Receptors, G-Protein-Coupled; D011957:Receptors, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009271:Naltrexone; D020881:Enkephalin, D-Penicillamine (2,5)-