Natural products for the treatment of pain: chemistry and pharmacology of salvinorin A, mitragynine and collybolide

Pain remains a very pervasive problem throughout medicine. Classical pain management is achieved through the use of opiates belonging to the mu opioid receptor (MOR) class which have significant side effects that hinder their utility. Pharmacologists have been trying to develop opioids devoid of side effects since the isolation of morphine from papaver somniferum, more commonly known as opium by Sertürner in 1804. The natural products salvinorin A, mitragynine and collybolide represent three non-morphinan natural product-based targets which are potent selective agonists of opioid receptors, and emerging next-generation analgesics. In this work, we review the phytochemistry, medicinal chemistry efforts on these templates and their effects on affinity, selectivity, analgesic actions and a myriad of other opioid receptor related behavioral effects.