Selective opioid growth factor receptor antagonists based on a stilbene isostere

[Display omitted] 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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2017-08, Vol.25 (16), p.4464-4474
Main Authors: Stockdale, David P., Titunick, Michelle B., Biegler, Jessica M., Reed, Jessie L., Hartung, Alyssa M., Wiemer, David F., McLaughlin, Patricia J., Neighbors, Jeffrey D.
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacology
Animals
Cell Line, Tumor
Cell Proliferation - drug effects
Cercopithecus aethiops
COS Cells
Dose-Response Relationship, Drug
Humans
Low-dose naltrexone
Molecular Structure
Opioid growth factor
Opioid receptor
Pawhuskin
Receptors, Opioid - metabolism
Stilbene isostere
Structure-Activity Relationship
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Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2017.06.035