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Bioorg Med Chem. 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.

Author information

1
Department of Chemistry, The University of Iowa, Iowa City, IA 52242-1294, United States.
2
Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.
3
Department of Pharmacology and Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Pennsylvania State University Cancer Institute, Hershey, PA 17033, United States.
4
Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Pennsylvania State University Cancer Institute, Hershey, PA 17033, United States.
5
Department of Pharmacology and Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Pennsylvania State University Cancer Institute, Hershey, PA 17033, United States. Electronic address: jneighbors@hmc.psu.edu.

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

PMID:
28693915
PMCID:
PMC5567982
DOI:
10.1016/j.bmc.2017.06.035
[Indexed for MEDLINE]
Free PMC Article

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