Stilbenes as κ-Selective, Non-nitrogenous Opioid Receptor Antagonists

Abstract

The natural stilbene pawhuskin A has been shown to function as an opioid receptor antagonist, with preferential binding to the κ receptor. This finding encouraged assembly of a set of analogues to probe the importance of key structural features. Assays on these compounds determined that one (compound 29) shows potent opioid receptor binding activity and significantly improved selectivity for the κ receptor. These studies begin to illuminate the structural features of these non-nitrogenous opioid receptor antagonists that are required for activity.

A selective delta opioid receptor antagonist based on a stilbene core

“…10–12 Our studies of the pawhuskins have led to the synthesis of pawhuskin A ( 1 ) 13 and C ( 2 ) 14 (Figure 1) as well as several analogues, and to the demonstration that compound 1 is a moderately selective KOP antagonist. During these explorations we synthesized compound 3 , 15 with the prenyl group on the “left-half” of the molecule (the portion biochemically derived from shikimate) placed in a different orientation than in the parent pawhuskin A. To our surprise, this regioisomer turned out to be an opioid receptor antagonist with high selectivity for the KOP (δ/κ > 67 and δ/μ > 67) and to be a bit more potent than pawhuskin A (K e = 0.15 μM vs. 0.20 μM).…”

“…To our surprise, this regioisomer turned out to be an opioid receptor antagonist with high selectivity for the KOP (δ/κ > 67 and δ/μ > 67) and to be a bit more potent than pawhuskin A (K e = 0.15 μM vs. 0.20 μM). 15 …”

“…An Arbuzov reaction was carried out by heating the bromide with triethyl phosphite to give the desired phosphonate 8 in moderate yield. Horner-Wadsworth-Emmons coupling of phosphonate 8 and the known aldehyde 9 15 afforded the protected stilbene 10 (Scheme 2). Global deprotection of the methoxymethyl ether groups by treatment with p -toluenesulfonic acid in methanol gave the desired analogue 4 .…”

Analgesic Potential of Extracts and Derived Natural Products from Medicinal Plants

“…Pawhuskin A has recognized to function as an opioid receptor antagonist, with special binding to the k receptor. Pawhuskin A is the most active natural compound making a small group of nonnitrogenous compounds with effect on the opiate receptor system [56].…”

Selective opioid growth factor receptor antagonists based on a stilbene isostere

“…Because of a long running interest in the synthesis and biology of prenylated stilbenes,[59, 60] we undertook the total synthesis and testing of this compound and demonstrated that it is a selective KOR antagonist. [61, 62] Subsequently, a medicinal chemistry program was established which has resulted in the synthesis of both DOR (2)[63, 64] and KOR (3)[63, 64] selective antagonists that are analogues of the natural product. These compounds are structurally unrelated to the classical opioids, and do not have the basic nitrogen found in morphine and other clinically used compounds such as meperidine, fentanyl or the antagonist naltrexone.…”