Discovery of Potent Kappa Opioid Receptor Agonists Derived from Akuammicine.

Akuammicine (), an alkaloid isolated from , is an agonist of the kappa opioid receptor (κOR). To establish structure-activity relationships (SARs) for this structurally unique κOR ligand, a collection of semisynthetic derivatives was synthesized. Evaluating these derivatives for their ability to activate the κOR and mu opioid receptor (μOR) revealed key SAR trends and identified derivatives with enhanced κOR potency.

Modified Akuamma Alkaloids with Increased Potency at the Mu-opioid Receptor.

Akuammine () and pseudoakuammigine () are indole alkaloids found in the seeds of the akuamma tree (). Both alkaloids are weak agonists of the mu opioid receptor (μOR); however, they produce minimal effects in animal models of antinociception. To probe the interactions of and at the opioid receptors, we have prepared a collection of 22 semisynthetic derivatives.

Isolation and Pharmacological Characterization of Six Opioidergic Alkaloids.

The seeds of the akuamma tree () have been used as a traditional treatment for pain and fever. Previous studies have attributed these effects to a series of indole alkaloids found within the seed extracts; however, these pharmacological studies were significantly limited in scope. Herein, an isolation protocol employing pH-zone-refining countercurrent chromatography was developed to provide six of the akuamma alkaloids in high purity and quantities sufficient for more extensive biological evaluation.