Indole Alkaloids of a Thai Medicinal Herb,Mitragyna speciosa,that has Opioid Agonistic Effect in Guinea-Pig Ileum

Abstract

Recently, we found that mitragynine, a major constituent of Mitragyna speciosa, has an opioid agonistic activity, but its weak potency could not explain the opium-like effect of this plant. In the present study, bioassay-guided fractionation of the crude extract of the leaves of M. speciosa was carried out to search for potent opioid agonists other than mitragynine. Opioid agonistic activities were evaluated using twitch contraction induced by electrical stimulation in guinea-pig ileum. The crude extract of M. speciosa inhibited the twitch contraction in a concentration-dependent manner. The inhibition was reversed by naloxone. The opioid effect was detected only in the crude base fraction, which was followed by the isolation of five indole alkaloids. Among these alkaloids, 7-hydroxymitragynine showed the most potent opioid effect on the electrically-stimulated contraction (pD (2) = 8.38 +/- 0.12). The potency, calculated using pD (2) values, was 30- and 17-fold higher than that of mitragynine and morphine, respectively. Antagonism of naloxone on concentration-response curves for 7-hydroxymitragynine confirmed its opioid effect. These results suggest that the opioid effect of M. speciosa is mostly based on the activity of 7-hydroxymitragynine.

Orally Active Opioid μ/δ Dual Agonist MGM-16, a Derivative of the Indole Alkaloid Mitragynine, Exhibits Potent Antiallodynic Effect on Neuropathic Pain in Mice

“…This medicinal herb contains many indole alkaloids (Takayama, 2004). (E)-Methyl 2- ((2S,3S,7aS,12bS)-3-ethyl-7a-hydroxy-8-methoxy-1,2,3,4,6,7,7a,12b-octahydroindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate (7-hydroxymitragynine), a main active constituent of this plant, is an indole alkaloid that is structurally different from morphine (Horie et al, 2005). We have reported that 7-hydroxymitragynine induces a potent antinociceptive effect on mouse acute pain through the activation of m-opioid receptors.…”

Suspected Adulteration of Commercial Kratom Products with 7-Hydroxymitragynine

“…We have found multiple packaged commercial Kratom products to contain artificially elevated concentrations of 7-hydroxymitragynine, the alkaloid responsible for M. speciosa's concerning mechanistic and side effect profile [20][21][22]. The amount of 7-hydroxymitragynine exceeded that found in naturally occurring material by up to 500 %.…”

“…Accounting for roughly 2 % of the plant's alkaloid content [16], 7-hydroxymitragynine is an opioid receptor agonist (like mitragynine) but demonstrates potent mu and kappa receptor selectivity [12]. This alkaloid is the major contributing factor for Kratom's analgesic properties, demonstrating opioid receptor affinity up to 17 times that of morphine [20][21][22]. It may also contribute to problematic Kratom use, which has been reported numerous times in the literature [10,[23][24][25][26].…”

Chemistry and Pharmacology of Analgesic Indole Alkaloids from the Rubiaceous Plant, Mitragyna speciosa

“…The crude base fraction was found to also inhibit twitch contraction. 24,25) To clarify the active principle in the alkaloidal fraction, the crude base was separated by column chromatography as mentioned above (Section 2.1) to give five alkaloids including one new compound. Initially, several pharmacological evaluations of the major alkaloid, mitragynine (1), were performed to give the following significant results.…”