Selective opioid growth factor receptor antagonists based on a stilbene isostere

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.

Synthesis and Antimicrobial Activity of δ-Viniferin Analogues and Isosteres

“…Amide isosteres of resveratrol have shown activity similar to the parent compound [31]. The amide linkage should allow to maintain the transoid architecture of the trans-stilbene, conferring however improved solubility and increased polarity [32,33] as well as differences in electronic perturbations [32,33]. Therefore, analogue 15 was synthesized (Scheme 2).…”

Triazoles in Medicinal Chemistry: Physicochemical Properties, Bioisosterism, and Application

“…159 Substitution of the alkene bond with 1,2,3-triazole or amide bonds has yielded analogues with good biological activities. 152,160,161 Among these, compounds 21b and 21a exhibit comparable biological activity against the glioblastoma-derived cell line SF295 (Figure 30B). 152 6.3.…”

“…Due to issues such as isomerization and dimerization of the alkenes, replacing the alkene with triazole helps to avoid these problems . Substitution of the alkene bond with 1,2,3-triazole or amide bonds has yielded analogues with good biological activities. ,, Among these, compounds 21b and 21a exhibit comparable biological activity against the glioblastoma-derived cell line SF295 (Figure B) …”