Putative kappa opioid heteromers as targets for developing analgesics free of adverse effects

Morgan Le Naour, Mary M. Lunzer, Michael D. Powers, Alexander E. Kalyuzhny, Michael A. Benneyworth, Mark J. Thomas, Philip S. Portoghese

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


It is now generally recognized that upon activation by an agonist, β-arrestin associates with G protein-coupled receptors and acts as a scaffold in creating a diverse signaling network that could lead to adverse effects. As an approach to reducing side effects associated with κ opioid agonists, a series of β-naltrexamides 3-10 was synthesized in an effort to selectively target putative κ opioid heteromers without recruiting β-arrestin upon activation. The most potent derivative 3 (INTA) strongly activated KOR-DOR and KOR-MOR heteromers in HEK293 cells. In vivo studies revealed 3 to produce potent antinociception, which, when taken together with antagonism data, was consistent with the activation of both heteromers. 3 was devoid of tolerance, dependence, and showed no aversive effect in the conditioned place preference assay. As immunofluorescence studies indicated no recruitment of β-arrestin2 to membranes in coexpressed KOR-DOR cells, this study suggests that targeting of specific putative heteromers has the potential to identify leads for analgesics devoid of adverse effects.

Original languageEnglish (US)
Pages (from-to)6383-6392
Number of pages10
JournalJournal of medicinal chemistry
Issue number15
StatePublished - Aug 14 2014


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