Mitragynine and its potential blocking effects on specific cardiac potassium channels

Tay, Yea Lu; Teah, Yi Fan; Chong, Yoong Min; Jamil, Mohd Fadzly Amar; Kollert, Sina; Adenan, Mohd Ilham; Wahab, Habibah A.; Döring, Frank; Wischmeyer, Erhard; Tan, Mei Lan

doi:10.1016/j.taap.2016.05.022

Cited by 16 publications

(17 citation statements)

References 72 publications

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“…Interestingly, mitragynine demonstrated a concentration-dependent inhibition on the hERG1a/1b current with an IC 50 value of 332.70 nM ( h = 0.61), which was rather similar to positive control drugs, for instance, propafenone and fluoxetine. The IC 50 value was slightly lower than the previously determined IC 50 values for mitragynine in hiPSC-CMs (0.91 μM), hERG1a-transfected HEK293 cells (1.62 μM) and hERG1a-injected Xenopus oocytes (1.03 μM) 49,50 . It is important to observe that the low IC 50 values are also close to the mitragynine concentrations in postmortem blood samples, ranging from 0.57 μM to 2.66 μM 12,13,41 .…”

Section: Discussioncontrasting

confidence: 71%

“…Mitragynine at 10 µM significantly prolonged the action potential duration (APD) at 50 and 90% repolarization respectively (APD50 and APD90) 49 . In addition, mitragynine was also found to inhibit the hERG1a and GIRK (G protein-coupled inward rectifier potassium) channels in other heterologous expression systems 50 . It was found to inhibit the hERG1a channel by interacting with the high-affinity binding sites, Y652 and F656 located in the S6 domain 50 .…”

Section: Discussionmentioning

confidence: 97%

“…In addition, mitragynine was also found to inhibit the hERG1a and GIRK (G protein-coupled inward rectifier potassium) channels in other heterologous expression systems 50 . It was found to inhibit the hERG1a channel by interacting with the high-affinity binding sites, Y652 and F656 located in the S6 domain 50 . It is likely that homomeric hERG1a and heteromeric hERG1a/1b channels share the same drug binding sites, as both hERG1a and hERG1b isoform share the common sequence in the putative transmembrane region (S1–S6) including the pore loop between S5 and S6.…”

Section: Discussionmentioning

confidence: 97%

“…In fact, more than 40% of hERG1 blockers presented combined acute channel blockade and trafficking defect 52,53 . Previous studies have suggested the potential of mitragynine in inhibiting hERG1a channel and I kr , but the effects of mitragynine on the channel trafficking were not fully elucidated 49,50 . Mitragynine was found to inhibit the protein expression of hERG1a, but the expression at the transcriptional level was not affected 50 .…”

Section: Discussionmentioning

confidence: 99%

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Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells

Tay

Amanah

Adenan

et al. 2019

Sci Rep

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Mitragyna speciosa Korth (M. speciosa) has been widely used as a recreational product, however, there are growing concerns on the abuse potentials and toxicity of the plant. Several poisoning and fatal cases involving kratom and mitragynine have been reported but the underlying causes remain unclear. The human ether-a-go-go-related gene 1 (hERG1) encodes the pore-forming subunit underlying cardiac rapidly delayed rectifier potassium current (IKr). Pharmacological blockade of the IKr can cause acquired long QT syndrome, leading to lethal cardiac arrhythmias. This study aims to elucidate the mechanisms of mitragynine-induced inhibition on hERG1a/1b current. Electrophysiology experiments were carried out using Port-a-Patch system. Quantitative RT-PCR, Western blot analysis, immunofluorescence and co-immunoprecipitation methods were used to determine the effects of mitragynine on hERG1a/1b expression and hERG1-cytosolic chaperones interaction. Mitragynine was found to inhibit the IKr current with an IC50 value of 332.70 nM. It causes a significant reduction of the fully-glycosylated (fg) hERG1a protein expression but upregulates both core-glycosylated (cg) expression and hERG1a-Hsp90 complexes, suggesting possible impaired hERG1a trafficking. In conclusion, mitragynine inhibits hERG1a/1b current through direct channel blockade at lower concentration, but at higher concentration, it upregulates the complexation of hERG1a-Hsp90 which may be inhibitory towards channel trafficking.

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Section: Discussioncontrasting

confidence: 71%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells

Tay

Amanah

Adenan

et al. 2019

Sci Rep

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“…The kratom alkaloids interact with additional cellular targets and are not limited to the opioid receptors. Indeed, reports have shown mitragynine binds to several non-opioid receptors, including adrenergic receptors and cardiac potassium channels [38,39]. However, determining the probable binding partners for a set of compounds is challenging considering that there are thousands of potential binding targets.…”

Section: Adrenergic and Serotonin Receptorsmentioning

confidence: 99%

Evaluating kratom alkaloids using PHASE

et al. 2020

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Kratom is a botanical substance that is marketed and promoted in the US for pharmaceutical opioid indications despite having no US Food and Drug Administration approved uses. Kratom contains over forty alkaloids including two partial agonists at the mu opioid receptor, mitragynine and 7-hydroxymitragynine, that have been subjected to the FDA's scientific and medical evaluation. However, pharmacological and toxicological data for the remaining alkaloids are limited. Therefore, we applied the Public Health Assessment via Structural Evaluation (PHASE) protocol to generate in silico binding profiles for 25 kratom alkaloids to facilitate the risk evaluation of kratom. PHASE demonstrates that kratom alkaloids share structural features with controlled opioids, indicates that several alkaloids bind to the opioid, adrenergic, and serotonin receptors, and suggests that mitragynine and 7-hydroxymitragynine are the strongest binders at the mu opioid receptor. Subsequently, the in silico binding profiles of a subset of the alkaloids were experimentally verified at the opioid, adrenergic, and serotonin receptors using radioligand binding assays. The verified binding profiles demonstrate the ability of PHASE to identify potential safety signals and provide a tool for prioritizing experimental evaluation of high-risk compounds.

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Clinical Pharmacology of the Dietary Supplement Kratom (Mitragyna speciosa)

Hartley

Bulloch

Penzak

2022

The Journal of Clinical Pharma

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Kratom (Mitragyna speciosa) consists of over 40 alkaloids, with 2 of them, mitragynine and 7-OH-mitragynine (7-OH-MG) being the main psychoactive compounds. Mitragynine and 7-OH-mitragynine each target opioid receptors and have been referred to as atypical opioids. They exert their pharmacologic effects on the mu, delta, and kappa opioid receptors. In addition, they affect adrenergic, serotonergic, and dopaminergic pathways. Kratom has been touted as an inexpensive, legal alternative to standard opioid replacement therapy such as methadone and buprenorphine. Other uses for kratom include chronic pain, attaining a "legal high," and numerous central nervous system disorders, including anxiety, depression, and posttraumatic stress disorder. Kratom induces analgesia and mild euphoria, with a lower risk of respiratory depression or adverse central nervous system effects compared to traditional opioid medications. Nonetheless, kratom has been associated with both physical and psychological dependence, with some individuals experiencing classic opioid withdrawal symptoms upon abrupt cessation. Kratom use has been linked to serious adverse effects, including liver toxicity, seizures, and death. These risks are often compounded by polysubstance abuse. Further, kratom may potentiate the toxicity of coadministered medications through modulation of cytochrome P450, P-glycoprotein, and uridine diphosphate glucuronosyltransferase enzymes. In 2016, the US Drug Enforcement Administration took steps to classify kratom as a federal schedule 1 medication; however, due to public resistance, this plan was set aside. Until studies are conducted that define kratom's role in treating opioid withdrawal and/or other central nervous system conditions, kratom will likely remain available as a dietary supplement for the foreseeable future.

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Mitragynine and its potential blocking effects on specific cardiac potassium channels

Cited by 16 publications

References 72 publications

Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells

Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells

Evaluating kratom alkaloids using PHASE

Clinical Pharmacology of the Dietary Supplement Kratom (Mitragyna speciosa)

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