Abstract
Covering: up to May 2025Since the isolation of morphine from opium, chemists have sought to modify its chemical structure in hopes of developing a safer, less addictive pain killer. At the same time, these novel morphine derivatives have provided new chemical tools to study the opioid receptors. In this way, the field of semi-synthesis, that is, the synthetic modification of isolated natural products, has co-evolved alongside the field of opioid pharmacology. This review summarizes recent semi-synthetic studies of the opioid-targeting natural products mitragynine, akuammine, akuammicine, and salvinorin A. These studies have resulted in novel opioid ligands with improved affinity and potency, differing signaling profiles, and increased effects in animals. In addition to offering new tools to study the opioid receptors, these natural product analogues represent promising steps towards developing safer opioid analgesics.