Date of Award
Ph.D. in Pharmaceutical Sciences
Christopher R McCurdy
Samir A. Ross
John M. Rimoldi
Opioid analgesics such as morphine and its derivatives are the most frequently prescribed narcotics for the treatment of severe and chronic pain. Among other side effects caused by the administration of these opioid analgesics, physical dependence and addiction are the most undesirable ones. Currently, pharmacological approaches to treat opioid dependence include mainly methadone and LAAM (mu-agonists), buprenorphine (mu-partial agonist) and clonidine (alpha2-adrenergic agonist). Considering the negative aspects of the relapsing nature correlated to opioid dependence, it is important to search for new ways to overcome this problem. The scope of this work is to study novel compounds based on the alkaloids present in Mitragynina speciosa (Korth), a tree indigenous to Southeast Asia. Consumption of leave extracts of this plant have been linked to the attenuation of the withdrawal syndrome associate with opioid dependence. Taking into consideration the structure of the major alkaloid, mitragynine, two classes of compounds were designed and synthesized: phenylpiperidines, including phenylaminopiperidines and phenylamidopiperidines, and tetrahydro-beta-carbolines. They were further submitted to in vitro evaluation on mu, delta and kappa-opioid receptors for their binding affinities. Out of six piperidines submitted to biological evaluation, four revealed significant affinity with Ki values in the micromolar range on either mu- and delta-receptors or kappa-opioid receptors. On the other hand, out of five tetrahydro-beta-carbolines tested, two showed kappa-receptors affinities in the nanomolar range. Although none of the compounds displayed binding affinities as high as mitragynine, it is possible to say that distinct moieties attached to the piperidines had different selectivities among mu-, delta- and kappa-opioid receptors. Tetrahydro-beta-carbolines, which mimics the four-ringed structure of mitragynine, showed only relevant affinity towards kappa-receptors. The important factor for the higher affinity of tetrahydro-beta-carbolines, when compared to piperidines, is that their less flexible structure is responsible for their greater affinity. More specifically, the methyl acetyl moiety at the C15 position had higher affinity than the methyl methoxyacrylate on kappa-receptors. Unfortunately, this work did not focus on stereoselective syntheses or chiral separations, which in the case of the chiral tetrahydro-beta-carbolines could have given valuable insights about the spatial requirements for affinity among the three main opioid receptors.
Arribas, Marco A., "Synthesis of Analogues Based on the Opioid Alkaloid Mitragynine" (2010). Electronic Theses and Dissertations. 1444.
Emphasis: Medicinal Chemistry