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PNAS 102 (25): 9050-9055

Copyright © 2005 by the National Academy of Sciences.

From the Cover


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

Maria Waldhoer *, Jamie Fong *, Robert M. Jones {dagger}, Mary M. Lunzer {ddagger}, Shiv K. Sharma {ddagger}, Evi Kostenis §, Philip S. Portoghese {ddagger}, ¶, and Jennifer L. Whistler *, ||

*Ernest Gallo Clinic and Research Center, University of California, San Francisco, CA 94608; {ddagger}Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455; {dagger}Department of Medicinal Chemistry, Arena Pharmaceuticals, San Diego, CA 92121; and §7TM Pharma, 2970 Hørsholm, Denmark

Edited by Richard P. Lifton, Yale University School of Medicine, New Haven, CT, and approved April 28, 2005

Received for publication February 9, 2005.

Abstract: 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.

Key Words: opioid

Author contributions: M.W., P.S.P., and J.L.W. designed research; M.W., J.F., and M.M.L. performed research; M.W., R.M.J., S.K.S., E.K., and P.S.P. contributed new reagents/analytic tools; M.W., M.M.L., P.S.P., and J.L.W. analyzed data; M.W., P.S.P., and J.L.W. wrote the paper; and E.K. edited the manuscript.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: GPCR, G protein-coupled receptor; DOP, delta opioid peptide; DOP-R, DOP receptor; KOP, kappa opioid peptide; KOP-R, KOP receptor; MOP, mu opioid peptide; MOP-R, MOP receptor; 6'-GNTI, 6'-guanidinonaltrindole; i.t., intrathecally; HA, hemagglutinin; NTI, naltrindole; NorBNI, nor-binaltorphimine.

See Commentary on page 8793.

To whom correspondence may be addressed at: Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455. E-mail: porto001{at} ||To whom correspondence may be addressed at: Ernest Gallo Research Center, University of California at San Francisco, 5858 Horton Street, Suite 200, Emeryville, CA 94608. E-mail: shooz2{at}

© 2005 by The National Academy of Sciences of the USA

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