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Other names | Spiro(2H-indole-2,1'(5'H)-indolizine)-7'-acetic acid, 6'-ethyl-1,2',3,3',6',7',8',8'a-octahydro-4-methoxy-alpha-(methoxymethylene)-3-oxo-, methyl ester, (alphaE,1'S,6'S,7'S,8'as)- |
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Formula | C23H30N2O5 |
Molar mass | 414.502 g·mol−1 |
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Mitragynine pseudoindoxyl is a rearrangement product of 7-hydroxymitragynine an active metabolite of mitragynine. [1] It is an analgesic being more potent than morphine. [2] [3]
Mitragynine pseudoindoxyl is a μ opioid receptor agonist and δ opioid receptor antagonist and acts as a G protein biased agonist at μ opioid receptors and possesses a favourable side effect profile compared to conventional opioids. [4] Cryo-EM structures of μOR-Gi1 complex with mitragynine pseudoindoxyl and lofentanil (one of the most potent opioids) revealed that the two ligands engage distinct subpockets, and molecular dynamics simulations showed additional differences in the binding site that promote distinct active-state conformations on the intracellular side of the receptor where G proteins and β-arrestins bind. [5] Importantly, studies have shown that oxidative metabolism is capable of transforming mitragynine (the main alkaloid in kratom) into mitragynine pseudoindoxyl in two steps, which is likely to influence kratom's complex pharmacological effects. [6] [7] [8]
Mitragynine pseudoindoxyl was first accessible via biomimetic semisynthesis from mitragynine. [2] [3] [4] Total synthesis of an unnatural analogue was reported featuring an interrupted Ugi reaction as the key step. [9] Scalable and modular total synthesis of the natural product has been also accomplished using a chiral pool based strategy. [10] [11] This study also demonstrated structural plasticity in biological systems.
Mitragyna speciosa is a tropical evergreen tree in the coffee family native to Southeast Asia. It is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea, where it has been used in herbal medicine since at least the 19th century. It has also historically been used for chewing, smoking, and tea. Kratom has opiate properties and some stimulant-like effects.
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ligare, which means 'to bind'. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein. The binding typically results in a change of conformational isomerism (conformation) of the target protein. In DNA-ligand binding studies, the ligand can be a small molecule, ion, or protein which binds to the DNA double helix. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure.
The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the OPRK1 gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering nociception, consciousness, motor control, and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.
The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(mu)-opioid peptide (MOP) receptors. The prototypical μ-opioid receptor agonist is morphine, the primary psychoactive alkaloid in opium and for which the receptor was named, with mu being the first letter of Morpheus, the compound's namesake in the original Greek. It is an inhibitory G-protein coupled receptor that activates the Gi alpha subunit, inhibiting adenylate cyclase activity, lowering cAMP levels.
The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligands. The regions of the brain where the δ-opioid receptor is largely expressed vary from species model to species model. In humans, the δ-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain.
Desmetramadol, also known as O-desmethyltramadol (O-DSMT), is an opioid analgesic and the main active metabolite of tramadol. Tramadol is demethylated by the liver enzyme CYP2D6 to desmetramadol in the same way as codeine, and so similarly to the variation in effects seen with codeine, individuals who have a less active form of CYP2D6 will tend to have reduced analgesic effects from tramadol. Because desmetramadol itself does not need to be metabolized to induce an analgesic effect, it can be used in individuals with low CYP2D6 activity unlike tramadol.
7-Hydroxymitragynine (7-OH) is a terpenoid indole alkaloid from the plant Mitragyna speciosa, commonly known as kratom. It was first described in 1994 and is a natural product derived from the mitragynine present in the kratom leaf. 7-OH binds to opioid receptors like mitragynine, but research suggests that 7-OH binds with greater potency.
Herkinorin is an opioid analgesic that is an analogue of the natural product salvinorin A. It was discovered in 2005 during structure-activity relationship studies into neoclerodane diterpenes, the family of chemical compounds of which salvinorin A is a member.
SNC-80 is an opioid analgesic compound that selectively activates μ–δ opioid receptor heteromers and is used in scientific research. It was discovered in 1994.
Rhynchophylline is an alkaloid found in certain Uncaria species (Rubiaceae), notably Uncaria rhynchophylla and Uncaria tomentosa. It also occurs in the leaves of Mitragyna speciosa (kratom) and Mitragyna tubulosa, a tree native to Thailand. Chemically, it is related to the alkaloid mitragynine.
An opioidergic agent is a chemical which functions to directly modulate the opioid neuropeptide systems in the body or brain. Examples include opioid analgesics such as morphine and opioid antagonists such as naloxone. Opioidergics also comprise allosteric modulators and enzyme affecting agents like enkephalinase inhibitors.
IBNtxA, or 3-iodobenzoyl naltrexamine, is an atypical opioid analgesic drug derived from naltrexone. In animal studies it produces potent analgesic effects that are blocked by levallorphan and so appear to be μ-opioid mediated, but it fails to produce constipation or respiratory depression, and is neither rewarding or aversive in conditioned place preference protocols. These unusual properties are thought to result from agonist action at a splice variant or heterodimer of the μ-opioid receptor, rather than at the classical full length form targeted by conventional opioid drugs.
Ciprefadol is an opioid analgesic that is an isoquinoline derivative most closely related to cyclazocine and picenadol, with a number of other related compounds known. Ciprefadol is a mixed agonist–antagonist at μ-opioid receptors and can partly block the effects of morphine at low doses, though at higher doses it acts more like a full agonist. It is also a potent κ-opioid agonist, unlike the corresponding N-methyl and N-phenethyl derivatives which are reasonably μ-selective agonists.
Iboga-type alkaloids are a set of monoterpene indole alkaloids comprising naturally occurring compounds found in Tabernanthe and Tabernaemontana, as well as synthetic structural analogs. Naturally occurring iboga-type alkaloids include ibogamine, ibogaine, tabernanthine, and other substituted ibogamines
. Many iboga-type alkaloids display biological activities such as cardiac toxicity and psychoactive effects, and some have been studied as potential treatments for drug addiction.Mitragynine is an indole-based alkaloid and the most abundant active alkaloid in the Southeast Asian plant Mitragyna speciosa, commonly known as kratom. The total alkaloid concentration in dried leaves ranges from 0.5 to 1.5%. In Thai varieties, mitragynine is the most abundant component while 7-hydroxymitragynine is a minor constituent. In Malaysian kratom varieties, mitragynine is present at lower concentration. Such preparations are orally consumed and typically involve dried kratom leaves which are brewed into tea or ground and placed into capsules. Mitragynine consumption for medicinal and recreation purposes dates back centuries, although early use was primarily limited to Southeast Asian countries such as Indonesia and Thailand where the plant grows indigenously. Recently, mitragynine use has spread throughout Europe and the Americas as both a recreational and medicinal drug. While research into the effects of kratom have begun to emerge, investigations on the active compound mitragynine are less common.
HS665 is a drug which acts as a potent and selective κ-opioid receptor agonist, and has analgesic effects in animal studies. HS665 is not an agonist for the mu receptor, leading to less potential for abuse.
SHR9352 is a drug which acts as a potent and selective biased agonist at the μ-opioid receptor, selective for activation of the G-protein signalling pathway over β-arrestin 2 recruitment. It was structurally derived from oliceridine by replacing the benzylic side chain with a cyclised group, although only some compounds in the series retained the desired biased agonist profile, with some derivatives such as compound 12 being potent, unbiased μ-opioid full agonists.
Speciociliatine is a major alkaloid of the plant Mitragyna speciosa, commonly known as kratom. It is a stereoisomer of Mitragynine and constitutes 0.00156 - 2.9% of the dried leaf material.
Collybolide is a secondary metabolite of the Rhodocollybia maculata mushroom, a basidiomycete fungus that grows on rotting conifer wood. It was previously believed to be a potent and selective kappa-opioid receptor agonist. However, a total synthesis and independent biological assay determined that collybolide neither excites nor suppresses kappa-opioid receptor signaling. Collybolide is unlikely to be psychoactive, although it has been shown to inhibit L-type calcium channels in isolated rat aorta.