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 journalArticle

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Abstract

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
Volume57
Issue number15
DOIs
StatePublished - Aug 14 2014

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Arrestin
Opioid Analgesics
Analgesics
HEK293 Cells
G-Protein-Coupled Receptors
Fluorescent Antibody Technique
Membranes

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Putative kappa opioid heteromers as targets for developing analgesics free of adverse effects. / Le Naour, Morgan; Lunzer, Mary M.; Powers, Michael D.; Kalyuzhny, Alexander E.; Benneyworth, Michael A; Thomas, Mark J; Portoghese, Philip S.

In: Journal of Medicinal Chemistry, Vol. 57, No. 15, 14.08.2014, p. 6383-6392.

Research output: Contribution to journalArticle

Le Naour, Morgan ; Lunzer, Mary M. ; Powers, Michael D. ; Kalyuzhny, Alexander E. ; Benneyworth, Michael A ; Thomas, Mark J ; Portoghese, Philip S. / Putative kappa opioid heteromers as targets for developing analgesics free of adverse effects. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 15. pp. 6383-6392.
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