Opioids produce potent analgesic effects through the activation of the mu-opioid receptor (μOR); however, this activation also produces adverse effects such as respiratory depression, tolerance, and dependence. Due to these deleterious side effects and the addictive nature of opioids, physicians have reduced the distribution of opioid prescriptions to patients. This has led some opioid users to turn to botanical supplements, such as akuamma, as alternative pain therapies. The bioactive compounds found in the seeds of the akuamma tree are a class of monoterpene indole alkaloids with moderate opioid receptor affinity. Specifically, the akuamma alkaloids akuammine and pseudoakuammigine can be isolated in high yields and are µOR agonists. Despite this activity, in our hands, pseudoakuammigine and akuammine produce minimal effects in animal models of antinociception, likely due to their modest potency at the µOR. Therefore, to aid in the design of more potent derivatives, we sought to establish structure-activity relationships that probe how these alkaloids interact with the opioid receptors. Toward this goal, here we report the synthesis of akuammine and pseudoakuammigine analogs utilizing highly chemoselective transformations to modify the C10, C11, C16, and N1 positions. The evaluation of these derivatives at the opioid receptors revealed key SAR trends and identified a compound with a 70-fold increase in potency at the μOR and a 7-fold increase in selectivity over the kappa opioid receptor. Ultimately, this new ligand class will be leveraged as chemical probes to study opioid receptor signaling and promising lead compounds for the development of safer analgesics.

Synthesis and evaluation of akuamma alkaloid analogues for alternative pain therapies

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