The
seeds of the akuamma tree (Picralima nitida) 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. Five of these
alkaloids, akuammine (1), pseudo-akuammigine (3), akuammicine (4), akuammiline (5), and
picraline (6), were evaluated against a panel of >40
central nervous system receptors to identify that their primary targets
are the opioid receptors. Detailed in vitro investigations revealed 4 to be a potent kappa opioid receptor agonist, and three
alkaloids (1–3) were shown to have
micromolar activity at the mu opioid receptor. The mu opioid receptor
agonists were further evaluated for analgesic properties but demonstrated
limited efficacy in assays of thermal nociception. These findings
contradict previous reports of the antinociceptive properties of the P. nitida alkaloids and the traditional use of akuamma seeds
as analgesics. Nevertheless, their opioid-preferring activity does
suggest the akuamma alkaloids provide distinct scaffolds from which
novel opioids with unique pharmacologic properties and therapeutic
utility can be developed.