Planta Med 2012; 78 - P_91
DOI: 10.1055/s-0032-1307599

Effects of Mitragynine and its Derivatives on Human Opioid Receptors (Delta, Kappa, and Mu)

O Dale 1, G Ma 1, C Gemelli 1, A Husni 1, C McCurdy 1, BA Avery 2, JF Leon 3, EB Furr 1, SP Manly 4, S Cutler 1
  • 1Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, MS 38677
  • 2Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, University, MS 38677
  • 3Instituto de Productos Naturales y Agrobiologica, Canary Islands, Spain 38206
  • 4National Center for Natural Products Research, Thad Cochran Research Center, University, MS 38677

Mitragynine is the most abundant and active indole alkaloid in the plant Mitragyna speciosa, commonly known as Kratom. At low doses, it is reported to have stimulatory effects through adrenergic receptors, but at higher doses opiate-like effects such as analgesia are reported [1]. Extracts of this plant are orally-active and attenuate the effects of opioid withdrawal [2]. This activity is modulated through the opioid receptors, primarily mu [3]. Mitragynine and four of its derivatives, mitraphylline, ajmalicine, 7-hydroxymitragynine, and paynantheine were tested and further characterized in competitive binding assays and a newly developed live-cell functional assay in the three human opioid receptors, delta, kappa, and mu. The assay monitors the decrease of forskolin stimulation in response to the test compound in these Gi-linked G-protein coupled opioid receptors through a transiently transfected luciferase tracer. As expected, mitragynine and related compounds showed the highest binding affinity to the mu opioid receptor. All five of the compounds showed agonistic activity to the three opioid receptors with the most active EC50's at the mu opioid receptor as well. Rank order was determined for mitragynine and its four derivatives through binding and functional activity at the three opioid receptors, and a novel, inexpensive, non-radioactive functional assay has been established for testing of further compounds. Acknowledgements: The project described was supported by Grant Number 5P20RR021929 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. This investigation was conducted in a facility constructed with support from research facilities improvement program C06 RR-14503–01 from the NIH National Center for Research Resources. References: [1] Matsumoto, et al. (1996) Eur J Pharmacol 317: 75–81. [2] Vicknasingam, et al. (2010) International Journal of Drug Policy 21: 283–288. [3] Matsumoto, et al. (2004) Life Sciences 74: 2143–2155.