Studies on the Determination of the Pharmacophoric Elements of the Naturally Occurring Opioid Receptor Agonist, Mitragynine and Related Alkaloids from Mitragyna speciosa

Leaves from the Southeast Asian tree Mitragyna speciosa, have been traditionally utilized for their ability to attenuate opium withdrawal and addiction. Mitragynine is the major alkaloid in this species and has been reported to be a partial opioid agonist. Moreover, the oxidative derivative, 7-hydroxymitragynine, a minor component, has been reported to be a full opioid agonist. Over 20 other alkaloids have been isolated from the tree yet all have not been characterized for opioid receptor affinity. We have isolated several known compounds from the dried leaves and produced simplified synthetic analogs of mitragynine in order to determine the active pharmacophore at opioid receptors. In a similar fashion to morphine-related synthetic ligands, we have systematically removed certain portions of the structure to determine the necessary structural requirements for opioid receptor affinity and activity. Known alkaloids and synthetic derivatives were screened on MOP, KOP, and DOP for opioid receptor affinities and some were screened in functional assays of GTPgS. Some of these compounds have shown interesting affinity at the opioid receptor subtypes as well as agonist and antagonist activities. Together, these data start to decipher the structural requirements of opioid receptor activity of mitragynine and related analogs. Additional synthetic modifications as well as in vivo studies may provide insights to novel analgesics and potential treatments for opioid withdrawal/addiction.