Induced association of μ opioid (MOP) and type 2 cholecystokinin (CCK 2) receptors by novel bivalent ligands

Yaguo Zheng, Eyup Akgiin, Kaleeckal G. Harikumar, Jessika Hopson, Michael D. Powers, Mary M. Lunzer, Laurence J. Miller, Philip S. Portoghese

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Both μ-opioid (MOP) and type 2 cholecystokinin (CCK 2) receptors are present in areas of the central nervous system that are involved in modulation of pain processing. We conducted bioluminescence resonance energy transfer (BRET) studies on COS cells coexpressing MOP and CCK 2 receptors to determine whether receptor heterodimerization is involved in such modulation. These studies revealed the absence of constitutive or monovalent ligand-induced heterodimerization. Heterodimerization of MOP and CCK 2 receptors therefore is unlikely to be responsible for the opposing effects between morphine and CCK in the CNS. However, association was induced, as indicated by a positive BRET signal, on exposure of the cells to bivalent ligands containing μ-opioid agonist and CCK 2 receptor antagonist pharmacophores linked through spacers containing 16-22 atoms but not with a shorter (9-atom) spacer. These studies demonstrate for the first time that an appropriately designed bivalent ligand is capable of inducing association of G-protein-coupled receptors. The finding that opioid tolerance studies with these ligands in mice showed no correlation with the BRET data is consistent with the absence of association of MOP and CCK 2 receptors in vivo.

Original languageEnglish (US)
Pages (from-to)247-258
Number of pages12
JournalJournal of Medicinal Chemistry
Volume52
Issue number2
DOIs
StatePublished - Jan 22 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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