The akuamma alkaloids are a class of monoterpenoid indole alkaloids with activity at the opioid receptors. Due to the structural differences between the akuamma alkaloids and the morphinan scaffold of traditional opioid analgesics, the akuamma alkaloids represent a unique opportunity to investigate the opioid receptors, which in turn, could lead to the development of safer treatments for pain. We recently developed a streamlined process for isolating six alkaloids from the seeds of the akuamma tree. The most abundant of these alkaloids, akuammine, is isolated in high purity and yield. We have now leveraged this material to investigate the structure-activity relationship (SAR) of akuammine at the mu-opioid receptor (MOR). A series of highly chemoselective reactions were used to generate a collection of akuammine derivatives. Further manipulation of the akuammine scaffold through structural rearrangements of the core provided a parallel series based on the related alkaloids cabuamine and vincorine. The synthesized compounds were evaluated at the opioid receptors to reveal SAR trends for these understudied class of alkaloids.

Probing the structure-activity relationship of opioidergic indole alkaloids isolated from akuamma seeds

ACS Spring Meeting 2021

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