MGM-9, a derivative of the indole alkaloid mitragynine
MGM-9, a derivative of the indole alkaloid mitragynine: A novel dual-acting mu- and kappa-opioid agonist with potent antinociceptive ["reducing sensitivity to painful stimuli"] and weak rewarding effects in mice.
By the Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, 1 Gumyo, Togane, Chiba 283-8555, Japan, published August 2008.
Mitragynine is a major indole alkaloid isolated from the Thai medicinal plant Mitragyna speciosa that has opium-like properties, although its chemical structure is quite different from that of morphine. We attempted to develop novel analgesics derived from mitragynine, and thus synthesized the ethylene glycol-bridged and C10-fluorinated derivative of mitragynine, MGM-9 [(E)-methyl 2-(3-ethyl-7a,12a-(epoxyethanoxy)-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-8-methoxyindolo [2,3-a] quinolizin-2-yl)-3-methoxyacrylate].
We hypothesized that a dual-acting mu- and kappa-opioid agonist could produce potent antinociceptive effects with fewer rewarding effects compared with mu agonists.
In this study, MGM-9 exhibited high affinity for mu- and kappa-opioid receptors with Ki values of 7.3 and 18nM, respectively. MGM-9 showed a potent opioid agonistic effect, and its effects were meditated by mu- and kappa-opioid receptor mechanisms in in vitro assays. Subcutaneous and oral administration of MGM-9 produced potent antinociceptive effects in mouse tail-flick, hot-plate, and writhing tests.
When administered orally, the antinociceptive effect of MGM-9 was seven to 22 times more potent than that of morphine. The antinociceptive effects of MGM-9 were mediated by both mu- and kappa-opioid receptors. Subcutaneous administration of MGM-9 twice daily for 5 days led to antinociceptive tolerance. In the gastrointestinal transit study, MGM-9 inhibited gastrointestinal transit, but its effect was weaker than that of morphine at equi-antinociceptive doses. Furthermore, MGM-9 induced less hyperlocomotion and fewer rewarding effects than morphine. The rewarding effect of MGM-9 was blocked by a mu antagonist and enhanced by a kappa antagonist.
Taken together, the results suggest that MGM-9 is a promising novel analgesic that has a stronger antinociceptive effect and weaker adverse effects than morphine.
Source: PubMed