174418-82-7

Usage

Uses

Used in Pharmaceutical Applications:
7-Hydroxy Mitragynine is used as an active alkaloid for its potent opioid agonistic activity. Its high affinity for A-opioid receptors in binding assays and its higher potency compared to mitragynine and morphine make it a valuable compound for the development of pharmaceutical products targeting opioid receptors.
Used in Pain Management:
Due to its potent opioid agonistic activity, 7-Hydroxy Mitragynine is used as an analgesic agent for pain management. Its higher potency compared to other opioids suggests potential applications in the treatment of severe pain conditions, where conventional opioids may not be as effective.
Used in Research and Development:
7-Hydroxy Mitragynine serves as an important compound in the research and development of new drugs targeting the opioid system. Its unique properties and high potency make it a valuable tool for understanding the mechanisms of opioid action and for the development of novel therapeutic agents with improved efficacy and reduced side effects.
Used in Drug Delivery Systems:
Similar to gallotannin, 7-Hydroxy Mitragynine could potentially benefit from novel drug delivery systems to enhance its applications and efficacy. The development of carriers such as organic and metallic nanoparticles could improve the delivery, bioavailability, and therapeutic outcomes of 7-Hydroxy Mitragynine in various applications, including pain management and pharmaceutical research.

Preparation

7-Hydroxymitragynine is produced by oxidation of mitragynine and is a minor constituent (< 0.01% in fresh leaves) found at concentrations of up to 2% in leaf extracts and commercial kratom products; however, it is believed to be the major contributor to the known addictive potential of kratom given its activity as a potent μ-opioid receptor agonist.

Pharmacokinetics

Mitragynine and 7-hydroxymitragynine are partial agonists at the mu-opioid receptor. Human studies demonstrate the analgesic effects of kratom, while kratom extract, mitragynine and 7-hydroxymitragynine have been shown to be antinociceptive in animal models. The antinociceptive effects are reversed by an opioid antagonist.Mitragynine also binds to adrenergic receptors, serotonergic and dopamine receptors. Although there is limited information regarding its effects at these receptors, kratom extracts and mitragynine have been reported in animal studies to have a variety of non-opioid-like behavioural effects, including antidepressant and antipsychotic effects.

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Relevant academic research and scientific papers

Site selective C–H functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy

Mitragynine (MG) is the most abundant alkaloid component of the psychoactive plant material “kratom”, which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We have developed a synthetic method for selective functionalization of the unexplored C11 position of the MG scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. Through this work we discover that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy. 7-Hydroxymitragynine (7OH), the parent compound with low efficacy on par with buprenorphine, is transformed to an?even lower efficacy agonist by introducing a fluorine substituent in this position (11-F-7OH), as demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid medications with mitigated adverse effects.

Stereochemical assignment of pseudoindoxyl alkaloids

The stereochemistries of the C2 and C3 positions in three pseudoindoxyl alkaloids, i.e., mitragynine pseudoindoxyl, yohimbine pseudoindoxyl, and β-yohimbine pseudoindoxyl, were elucidated by spectroscopic analyses. The CD spectra of these compounds and that of fluorocarpamine showed the antipodal-like curves in the long wavelength region.

Lateral Flow Assessment and Unanticipated Toxicity of Kratom

The leaves of the Mitragynine speciosia tree (also known as Kratom) have long been chewed, smoked, or brewed into a tea by people in Southeastern Asian countries, such as Malaysia and Thailand. Just this past year, the plant Kratom gained popularity in the United States as a "legal opioid" and scheduling it as a drug of abuse is currently pending. The primary alkaloid found in Kratom is a μ-opioid receptor agonist, mitragynine, whose structure contains a promising scaffold for immunopharmacological use. Although Kratom is regarded as a safe opioid alternative, here we report the LD50 values determined for its two main psychoactive alkaloids, mitragynine and 7-hydroxymitragynine, as comparable to heroin in mice when administered intravenously. Given Kratom's recent emergence in the U.S., there is currently no diagnostic test available for law enforcement or health professionals, so we sought to design such an assay. Mitragynine was used as a starting point for hapten design, resulting in a hapten with an ether linker extending from the C9 position of the alkaloid. Bacterial flagellin (FliC) was chosen as a carrier protein for active immunization in mice, yielding 32 potential monoclonal antibodies (mAbs) for assay development. Antimitragynine mAbs in the range of micro- to nanomolar affinities were uncovered and their utility in producing a convenient lateral flow detection assay of human fluid samples was examined. Antibodies were screened for binding to mitragynine, 7-hydroxymitragynine, and performance in lateral flow assays. Two monoclonal antibodies were subcloned and further purified with 93 and 362 nM affinity to mitragynine. Test strip assays were optimized with a detection cut off of 0.5 μg/mL for mitragynine in buffer and urine (reflecting projected clinically relevant levels of drug in urine), which could be beneficial to law enforcement agencies and health professionals as the opioid epidemic in America continues to evolve.

Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: Discovery of opioid agonists structurally different from other opioid ligands

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 μ-, δ-, and κ-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.

Oxidative Metabolism as a Modulator of Kratom's Biological Actions

The leaves of Mitragyna speciosa (kratom), a plant native to Southeast Asia, are increasingly used as a pain reliever and for attenuation of opioid withdrawal symptoms. Using the tools of natural products chemistry, chemical synthesis, and pharmacology, we provide a detailed in vitro and in vivo pharmacological characterization of the alkaloids in kratom. We report that metabolism of kratom's major alkaloid, mitragynine, in mice leads to formation of (a) a potent mu opioid receptor agonist antinociceptive agent, 7-hydroxymitragynine, through a CYP3A-mediated pathway, which exhibits reinforcing properties, inhibition of gastrointestinal (GI) transit and reduced hyperlocomotion, (b) a multifunctional mu agonist/delta-kappa antagonist, mitragynine pseudoindoxyl, through a CYP3A-mediated skeletal rearrangement, displaying reduced hyperlocomotion, inhibition of GI transit and reinforcing properties, and (c) a potentially toxic metabolite, 3-dehydromitragynine, through a non-CYP oxidation pathway. Our results indicate that the oxidative metabolism of the mitragynine template beyond 7-hydroxymitragynine may have implications in its overall pharmacology in vivo.

MITRAGYNINE ANALOGS FOR THE TREATMENT OF PAIN, MOOD DISORDERS AND SUBSTANCE USE DISORDERS

The present invention provides a compound having the structure (I): or a pharmaceutically acceptable salt or ester thereof, and a method of treating a subject afflicted with pain a depressive disorder, a mood disorder or an anxiety disorder by administering the compound to the subject.

DEUTERATED MITRAGYNINE ANALOGS AS SAFER OPIOID MODULATORS IN THE MITRAGYNINE CLASS

The present invention provides a compound having the structure: or a pharmaceutically acceptable salt or ester thereof, and methods of using the compound to treat pain, depressive disorders, mood disorders, anxiety disorders, opioid use disorder, and opioid withdrawal symptoms.

Method for preparing 7-hydroxymitragynine

The invention discloses a simple andconvenient method for synthesizing7-hydroxymitragynine, and belongs to the technical field of medicines. The method for preparing 7-hydroxymitragynine comprises the following steps:taking mitragynine as a starting material, and tetrahydrofuran and water as solvents, purifying an obtained crude product through alkaline column chromatography after reacting with [bis(trifluoroacetyl) iodine] benzene at the temperature of 0 DEG C in argon atmosphere, and preparing andobtaining7-hydroxymitragynine. The materials required by the invention are readily available, low in cost, simple in reaction operation and easy to process, and a large amount of7-hydroxymitragynine can be obtained for the use of medicine research and development.

MITRAGYNINE ALKALOIDS AS OPIOID RECEPTOR MODULATORS

The present invention provides a compound having the structure: or a pharmaceutically acceptable salt or ester thereof, and a method of treating a subject afflicted with pain, a depressive disorder, a mood disorder or an anxiety disorder by administering the compound to the subject.

MITRAGYNINE ANALOGS AND USES THEREOF

Described herein are compounds of Formulae (I')-(II'), compounds of Formulae (I)- (II) and pharmaceutically acceptable salts thereof. Compounds of the present invention are useful for modulating opioid receptor activity. The provided compounds may have both agonistic and antagonistic effect on one or more opioid receptors. Methods of using the compounds for treating or managing pain are also described.