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, 57 (15), 6383-92

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


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

Morgan Le Naour et al. J Med Chem.


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.


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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