Mitragynine and its analogues in kratom are indole alkaloids of the Corynanthe-type possessing a monoterpene (iridoid) moiety. Mitragynine is an alkaloid found in the leaves of the South East Asian treeMitragyna speciosa. Kratom leaves are chewed, smoked, or consumed in tea.696 Leaves from this tree have traditionally been used for both their stimulant properties and as an opium substitute. Mitragynine is a potent and selective µ-opioid agonist. It has been shown that the antinociceptive effects are mediated by its action on the supraspinal opioid, whereas its psychoactive effects may be mediated by central opioid receptors. Case reports of toxicity and death have been reported in polydrug exposure, including mytragynine. Although widespread use of kratom has not been documented in the United States, its use has been increasing in some locations.
Mitragynine is a corynanthe-type monoterpene indole alkaloid. Mitragynine congeners especially its diastereomers were found to be present in the leaves of M. speciosa which are speciogynine, speciociliatine, and mitraciliatine (Raffa, 2015). Since the diastereomeric phytoconstituents are congeners of mitragynine that have the tetracyclic indole alkaloid core structure, these compounds can be distinguished through the structural configuration at certain important positions (Ellis et al., 2020). Based on the chemical structure of these compounds, the difference in the configurational positioning at C-3, C-15, and C-20 results in the occurrence of mitragynine, speciogynine, speciociliatine, and mitraciliatine, respectively. The summary of absolute configurations (R or S) at the positioning of C-3, C-15, and C-20 of the respective compounds.
Despite the discovery of over 54 alkaloids from the leaves of M. speciosa, most research focused on the major constituent in the plant, which is mitragynine (Flores-Bocanegra et al., 2020). Historically, mitragynine (1) was first isolated by Ellen Field in 1921, and later, the structure was completely characterized and elucidated by Beckett and Zacharias in 1965 (Gogineni et al., 2015). Furthermore, the diastereomers of mitragynine, speciogynine, speciociliatine, and mitraciliatine were also reported to be isolated from the leaves of M. speciosa.
Based on the stereochemical configuration on the structure of mitragynine and its diastereomers at position C-3, mitragynine and speciogynine possesses a flat trans-quinolizidine conformation in the rings of C and D as compared with a cis-quinolizine conformation in speciociliatine (Takayama, 2004). In addition, speciociliatine has a different spatial arrangement in comparison with mitragynine, where both structures can be distinguished by a switch in the configuration from R [speciociliatine] to S mitragynine of the hydrogen moiety positioned at C-3. This configurational inversion from R to S will induce significant spatial change in the core skeleton of speciociliatine, where it will enhance its molecular volume while the inversion to mitragynine will cause the β-methoxy acrylate moiety in the compound to adopt an axial position (Berthold et al., 2021).
Isolation of Mitragynine (1) and its Diastereomers
The first isolation of mitragynine was reported by Field, a Scottish chemist in 1921 (Kruegel and Grundmann, 2018). Subsequently, Beckett et al. (1965) established the chemical structure of mitragynine while the absolute configuration of the compound was later confirmed by Zacharias et al. (1965) using the X-ray crystallographic method (Gogineni et al., 2015; Flores-Bocanegra et al., 2020). Raffa (2015) reported that decades later, the diastereomers of mitragynine, speciogynine, and speciociliatine were discovered and isolated by Beckett et al. (1965) and Shellard et al. (1978). Another diastereomer, mitraciliatine , was also reported from the leaves of M. speciosa (Flores-Bocanegra et al., 2020). The increased interest in the alkaloids of M. speciosa by natural products and medicinal chemists had led to an increasing amount of research conducted in isolating other phytoconstituents by using various chromatographic techniques. However, there are issues regarding the purity of the alkaloids isolated from M. speciosa due to the difficulty in separating and isolating isomeric alkaloids. Goh et al. (2021) found a fast and rapid method in the isolation of mitragynine with a peak purity of 98%, which was affirmed using HPLC analysis. Meanwhile, Chear et al. (2021) reported on the isolation of speciogynine and speciociliatine with high purity (≥98%) using column chromatographic techniques. These studies provide an understanding in solving the purity issue of the alkaloid drugs. It also prompted researchers to develop a set of guidelines to ensure that the purity (≥95%) is within the required guidelines as it is vital for preclinical and clinical studies.
Characterization of Mitragynine and Its Diastereomers
Complete characterization and elucidation of mitragynine and its diastereomers were reported recently by Flores-Bocanegra et al. (2020) and Chear et al. (2021) using nuclear magnetic resonance (NMR) and mass spectrometry (MS) analyses. Flores-Bocanegra et al. (2020) devised a simple and comprehensive decision tree to distinguish the indole and oxindole alkaloids discovered from M. speciosa through the identification of important chemical shifts such as 1H and 13C NMR signals. adapted from Flores-Bocanegra et al. (2020) where the flow of decision for the identification of mitragynine and its diastereomers, speciogynine, speciociliatine, and mitraciliatine, are comprehensively depicted. The references for spectral data of mitragynine.
The pharmacological activity of the alkaloids from M. speciosa has been extensively researched, focusing on the analgesic potency of the primary indole alkaloid, mitragynine. Isomeric indole alkaloids such as mitragynine speciogynine, and speciociliatine were assessed through in vivo and in vitro approaches for their pharmacological properties, especially in assessing their analgesic and toxicological properties. Takayama (2004) accumulated evidence implicating the opioid receptor system as the primary mediator of the central nervous system effects displayed by these isomeric phytoalkaloids. To the best of our knowledge, we found very limited pharmacological evidence on mitraciliatine. The pharmacological properties of these alkaloids are shown below.
Macko et al. (1972) first reported the pharmacological studies of mitragynine. The analgesic potency of mitragynine has been studied mostly through tail-flick and hot plate tests. It was found to induce antinociception in the brain. It was also reported that the antinociceptive action of mitragynine in mice was at least partly involved in the supraspinal opioid systems (Matsumoto et al., 1996). Currently, detailed pharmacology studies are being conducted on mitragynine and its diastereomers to understand their mechanism of action and their structure–activity relationship in pain management.
A preliminary study conducted by Takayama et al. (2002) on the biological activities of M. speciosa crude leave extract with several bioactive alkaloids showed promising results. The first noteworthy result was shown through the ability of mitragynine in inhibiting the twitch contraction of guinea pig ileum, which is induced by electrical stimulation. It was reported that the opioid agonistic activities of mitragynine and speciociliatine were evaluated based on their ability to inhibit contraction that stimulates the guinea pig ileum, which is reversed by a classical antagonist, naloxone.
Based on the in vitro studies conducted by Takayama et al. (2002), mitragynine was reported to have a significant binding affinity on the opioid receptor.
Mitragynine act as a partial agonist at MOR with a maximal efficacy of 34%. However, at KOR and DOR, the functional activity of mitragynine alkaloid converts from partial agonist to antagonist at lower potency. Additionally, the diastereomers of mitragynine, speciogynine, and speciociliatine showed null measurable agonist activity at all the opioid receptors and only revealed a weak antagonist effect. By comparing mitragynine and speciogynine, the ethyl group at position 20 on ring D shows a crucial point as the epimerization of this group is able to switch the agonistic activity to antagonist activity at MOR. The modification of the configuration of the ethyl group also reduced the binding affinity. carried out a pharmacological investigation on mitragynine and speciociliatine to evaluate its opioid binding affinities . The binding affinities of speciociliatine (Ki (MOR): 116 ± 36 nM, Ki (KOR): 54.5 ± 4.4 nM) at both opioid receptors are higher than mitragynine (1) (Ki (MOR): 198 ± 30 nM, Ki (KOR): 161 ± 10 nM). Berthold et al. (2021) also found that the binding affinity of speciociliatine (3) at MOR and KOR was 3.0- and 1.7-fold higher than that of mitragynine (1). Based on the two studies, it is suggested that the conversion of the configuration at position 3 from S [mitragynine (1)] to R [speciociliatine (3)] causes a significant change in terms of the binding affinities. This switch in conformation speciociliatine (3) will cause the molecular volume of speciociliatine (3) to have a larger space to bind and interact with the active sites of the opioid receptor and increase its binding affinities compared to mitragynine (1). Based on molecular docking studies, the acrylate moiety will affect the interaction with the key residue, which plays an important role in binding to the opioid receptors. However, these results were contrary to what was reported by Kruegel et al. (2016), who found that speciociliatine (3) had no significant agonist activity at all the human opioid receptors and acted as a weak antagonist. The difference might be due to different assay types used to evaluate speciociliatine (3). This result was confirmed by a study by Nickolls et al. (2011) that different types of assays used to evaluate the targeted compound will show different agonistic effects.
The ethyl group in ring D is extremely crucial in predicting the binding affinities at the opioid receptor. The ethyl group will act as a hydrophobic group that interacts with the receptor. For the binding affinities of the structure without the ethyl group, the binding affinities are diminished drastically as compared to mitragynine. All in all, the number of different stereochemical configurations in the diastereomers can retain to bind at MOR. Meanwhile, absolute stereochemistry is found to be crucial in agonistic activity in the opioid receptor.
A previous study had affirmed that mitragynine (1) displayed a suppressive effect on the central serotonin neurotransmission system. In mice, the suppression of 5-HT2A agonist (5-methoxy-N, N-dimethyltryptamine)-induced head twitch response was observed due to the effect from the pre-treatment with mitragynine (1), which showed that the principal kratom alkaloid acts as a competitive antagonist in blocking the stimulation of the 5-HT2A receptor. investigated the in vitro and in vivo activity of kratom alkaloids, especially mitragynine (1), speciogynine (2), and speciociliatine (3)
The benefits of Mitragynine from Kratom
Mitragynine is an alkaloid found in the leaves of the South East Asian tree Mitragyna speciosa.
Mitragynine is a potent and selective opioid agonist. It has been shown that the antinociceptive effects are mediated by its action on the supraspinal and opioid, whereas its psychoactive effects may be mediated by central opioid receptors.
The Effects of Mitragynine from Kratom
Mitragynine, is a naturally occurring indole alkaloid that can be isolated from the leaves of a psychoactive medicinal plant. Mitragyna speciosa, also known as kratom, is found to possess promising analgesic effects on mediating the opioid receptors such as µ (MOR), δ (DOR), and κ (KOR). This alkaloid has therapeutic potential for pain management as it has limited adverse effect compared to a classical opioid, morphine. Mitragynine is frequently regarded to behave like an opioid but possesses milder withdrawal symptoms. The use of this alkaloid as the source of an analgesic candidate has been proven through comprehensive preclinical and clinical studies. The present data have shown that mitragynine is able to bind to opioid receptors, particularly MOR, to exhibit the analgesic effect. Moreover, the chemical and pharmacological aspects of mitragynine and its diastereomers, speciogynine, speciociliatine, and mitraciliatine, are discussed. It is interesting to know how the difference in stereochemical configuration could lead to the difference in the bioactivity of the respective compounds. Hence, in this review, the updated pharmacological and toxicological properties of mitragynine and its diastereomers are discussed to render a comprehensive understanding of the pharmacological properties of mitragynine and its diastereomers based on their structure–activity relationship study.
Side effects of Mitragynine from Kratom
The study results findings revealed that, although in vitro studies had found the most abundant alkaloid of the K-Tea preparation — mitragynine — to cause a prolonged QTc interval and an increased risk of torsades de pointes, a clinical study examining regular consumption of K-Tea by humans did not report such results. Several case reports have also highlighted that K-Tea consumption is associated with ventricular arrhythmias and cardiac arrest, but this association may occur when kratom is co-administered with other substances.
