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, 57 (15), 6383-92

Putative Kappa Opioid Heteromers as Targets for Developing Analgesics Free of Adverse Effects

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Putative Kappa Opioid Heteromers as Targets for Developing Analgesics Free of Adverse Effects

Morgan Le Naour et al. J Med Chem.

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.

Figures

Figure 1
Figure 1
Intracellular Ca2+ release profiles at multiple opioid receptors HEK293 cells. aData are mean ± SEM (n = 3–5). RFU, relative fluorescence unit.
Figure 2
Figure 2
(A) 3 (INTA) did not produce aversion in mice. A strong dose-dependent rewarding effect was observed in a wide range of doses (0.3–10 mg/kg, sc). (B) On another hand, salvinorin A (0.3–1.0 mg/kg, sc) in the same protocol produced a strong aversion. (C) 3 condition preference was reversed by naloxone. *p < 0.05, **p < 0.01, ***p < 0.001; Bonferroni t test comparison versus vehicle control (same test). Test 1 and test 2 were performed following four and eight days of conditioning, respectively.
Figure 3
Figure 3
Representative high power fluorescent micrographs of control HEK293 cells and those singly and doubly expressing opioid receptors that were stained for β-arrestin2. INTA (3)- and NNTA-treated MOR-KOR HEK293 cells showed some recruitment of β-arrestin2, while INTA-treated KOR-DOR HEK293 cells showed no recruitment of β-arrestin2. 6′-GNTI-treated KOR-DOR HEK 293 cells exhibited little recruitment. Treatment of nontransfected HEK293 cells with 3, NNTA (1), 6′-GNTI (2), or any of the standard opioid control ligands did not induce β-arrestin2 recruitment (not shown).

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References

    1. Milligan G. G protein-coupled receptor dimerization: function and ligand pharmacology. Mol. Pharmacol. 2004, 66, 1–7. - PubMed
    2. Rachid A. J.; O’Dowd B. F.; George S. R. Diversity and complexity of signaling though peptidergic G protein-coupled receptors. Endocrinology 2005, 145, 2645–2652.
    1. Hiller C.; Kuehhorn J.; Gmeiner P. Class A G protein-coupled receptor (GPCR) dimers and bivalent ligands. J. Med. Chem. 2013, 56176542–6559. - PubMed
    1. Ferre S.; Baler R.; Bouvier M.; Caron M. G.; Devi L. A.; Durroux T.; Fuxe K.; George S. R.; Javitch J. A.; Lohse M. J.; Mackie K.; Milligan G.; Pfleger K. D. G.; Pin J.-P.; Volkow N.; Waldhoer M.; Woods A. S.; Franco R. Building a new conceptual framework for receptor heteromers. Nature Chem. Biol. 2009, 5, 131–134. - PMC - PubMed
    1. Angers S.; Salahpour A.; Bouvier M. Dimerization: an emerging concept for G protein-coupled receptor ontogeny and function. Annu. Rev. Pharmacol. Toxicol. 2002, 42, 409–435. - PubMed
    1. Gomes I.; Jordan B. A.; Gupta A.; Rios C.; Trapaidze N.; Devi L. A. G protein-coupled receptor dimerization: implications in modulating receptor function. J. Mol. Med. 2001, 79, 226–242. - PubMed

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