From Plant to Bench: Natural Products as Source for Analgesic Drug Development

The use of natural products as traditional medicines, remedies, potions and oils have been described since ancient times for the treatment of many diseases. Plant derived natural products, in particular, represent a successful source for potential drug leads. For instance, morphine, a mu opioid peptide receptor (MOPr) agonist, clinically used as analgesic, is an alkaloid isolated from opium poppy of Papaver somniferum. After its isolation, ongoing efforts in medicinal chemistry opened a wide program of research aimed to discover analogues that maintain the analgesic profile of morphine but reduced side effects. Analogously, mitragynine, an alkaloid isolated from the Thai medicinal plant Mitragyna speciosa, showed morphine-like properties in pain animal models although its chemical structure is different from that of morphine. Mitragynine has analgesic, muscle relaxant, anti-inflammatory, anorexic effects and, similarly to morphine, leads to tolerance and aversive withdrawal effects if chronically administered. Mitragynine actions involve MOPr, neuronal Ca2+ channels and monoaminergic system. Salvinorin A, extracted from Salvia divinorum, was used by Indian tribes of southern California as an aid in childbirth. It is a kappa opioid peptide receptor (KOPr) agonist with anti-addictive properties identified as a potential treatment for drug abuse. In this chapter Salvinorin A and Mitragynine pharmacological and chemical features, that made them suitable scaffolds for medicinal chemistry approaches, are described. Our efforts are focused on the description of SAR (structure-activity relationship) of salvinorin A and mitragynine derivatives developed to obtain a reduced burden of undesirable effects.

Keywords: Antinociception, Biased opioid ligands, Delta opioid receptor, Kappa opioid receptor, Mitragynine, Mu opioid receptor, Opioid, Pain, Salvinorin A, Structure-activity relationship.