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. 2017 Aug 15;25(16):4464-4474.
doi: 10.1016/j.bmc.2017.06.035. Epub 2017 Jun 27.

Selective Opioid Growth Factor Receptor Antagonists Based on a Stilbene Isostere

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Free PMC article

Selective Opioid Growth Factor Receptor Antagonists Based on a Stilbene Isostere

David P Stockdale et al. Bioorg Med Chem. .
Free PMC article

Abstract

As part of an ongoing drug development effort aimed at selective opioid receptor ligands based on the pawhuskin natural products we have synthesized a small set of amide isosteres. These amides were centered on lead compounds which are selective antagonists for the delta and kappa opioid receptors. The amide isomers revealed here show dramatically different activity from the parent stilbene compounds. Three of the isomers synthesized showed antagonist activity for the opioid growth factor (OGF)/opioid growth factor receptor (OGFR) axis which is involved in cellular and organ growth control. This cellular signaling mechanism is targeted by "low-dose" naltrexone therapy which is being tested clinically for multiple sclerosis, Crohn's disease, cancer, and wound healing disorders. The compounds described here are the first selective small molecule ligands for the OGF/OGFR system and will serve as important leads and probes for further study.

Keywords: Low-dose naltrexone; Opioid growth factor; Opioid receptor; Pawhuskin; Stilbene isostere.

Figures

Figure 1
Figure 1
Structures of Pawhuskin A (1) and related DOR and KOR selective antagonist analogues 2 and 3.
Figure 2
Figure 2
Compound 3 docked into the KOR ligand binding site. H-bonds with protein are shown in blue.
Figure 3
Figure 3
Structure of the amide compounds designed as stilbene isosteres.
Figure 4
Figure 4
Concentration response curves for β-arrestin recruitment assays of agonism in cells transfected with the human MOR, DOR and KOR. Positive controls for each receptor are shown as well.
Figure 5
Figure 5
Cell growth in COS-7 cells at 72 hours. Cells were treated with 1 μM concentration of the indicated compounds. * p < 0.05, ** p <0.005
Figure 6
Figure 6
Cell growth for COS-7 cells at 72 hours. Cells were treated with 1 μM concentration of compounds. Cell growth was assessed by incorporation of BrdU. * P < 0.05
Figure 7
Figure 7
Treatment of SKOV-3 human derived ovarian cancer cells with compound 4, 6, and 7 at 10 μM concentration showed enhanced cell growth at 96, and 120 hour time points with 24 hour (constant) drug treatment (Left Panels), and reduced growth at the same time points when the “low-dose naltrexone” regimen of pulsed therapy is used (Right Panels). Here the “low-dose” therapy is achieved by pulsing drug on for 6 hours every other day.
Figure 8
Figure 8
Treatment of SKOV-3 human derived ovarian cancer cells with compounds 6 and 7 at four concentration showed enhanced cell growth at the 120 hour time point with 24 hour (constant) drug treatment ( Upper Panel), and reduced growth at the same time point when the “low-dose naltrexone” regimen of pulsed therapy is used (Lower Panels).
Scheme 1
Scheme 1
Synthesis of amides 4 and 5.
Scheme 2
Scheme 2
Synthesis of compounds 6 and 7.

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