Studies on the Synthesis and Opioid Agonistic Activities of Mitragynine-Related Indole Alkaloids:  Discovery of Opioid Agonists Structurally Different from Other Opioid Ligands

Abstract

Mitragynine (1) is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa, and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compound, synthesis of some derivatives, evaluations of the structure-activity relationship, and surveys of the intrinsic activities and potencies on opioid receptors were performed with guinea pig ileum. The affinities of some compounds for mu-, delta-, and kappa-receptors were determined in a receptor binding assay. The essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were also clarified. The oxidative derivatives of mitragynine, i.e., mitragynine pseudoindoxyl (2) and 7-hydroxymitragynine (12), were found as opioid agonists with higher potency than morphine in the experiment with guinea pig ileum. In addition, 2 induced an analgesic activity in the tail flick test in mice.

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 %.…”

“…Mitragynine was isolated from dried leaves of M. speciosa as described by Ponglux et al [16]. Synthesis of 7-hydroxymitragynine was performed in-house as reported earlier by Takayama et al and Ponglux et al [16,21]. Purities of mitragynine and 7-hydroxymitragynine were determined by 1H nuclear magnetic resonance (NMR), 13C NMR, high performance liquid chromatography, elemental analysis, and high-resolution mass spectrometry.…”

“…Combined spiking stock solutions (CSSs) containing 10, 7.5, 4.5, 2.5, 1.25, 0.25, 0.125, and 0.05 μg/mL for calibration standards (CS) and 9, 5, 0.1 Fig. 1 Structures of mitragynine and 7-hydroxymitragynine Table 1 Central nervous system receptor binding data for mitragynine [10] Percentage inhibition of radioligand binding by mitragynine at selected receptor systems [21] and 0.05 μg/mL for quality control (QC) standards of each analyte were prepared by appropriately diluting the WS in acetonitrile. The CS containing 1, 2.5, 5, 25, 50, 90, 150, and 200 ng/mL of mitragynine and 7-hydroxymitragynine were prepared by diluting 2 μL of the individual CSS to 100 μL with methanol.…”

“…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].…”

Indolo[2,3-a]quinolizidines and Derivatives: Bioactivity and Asymmetric Synthesis

“…[37] 14 Graph 1 -Relative potency of seven compounds with interesting activities for opioid receptor. In tables 1 and 2 the reader can find a summary of the main biological properties described to date for Indolo[2,3-a]quinolizidines and derivatives.…”