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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.

Pawhuskin A is an isoprenylated stilbene that was isolated from Dalea purpurea and reported to have affinity for the opioid receptor in vitro. It has been synthesized through a convergent sequence that joins a prenylated aldehyde with a geranylated phosphonate in a stereoselective Horner-Wadsworth-Emmons condensation to afford the target E olefin isomer. This synthesis confirms the structure assigned to the natural product and establishes a route that may be used to explore its biological activity and to prepare more active analogues.