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| Other names | rotundine, hyndanrine |
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| ECHA InfoCard | 100.241.370 |
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| Formula | C21H25NO4 |
| Molar mass | 355.434 g·mol−1 |
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Tetrahydropalmatine (THP) is anisoquinoline alkaloid found in several different plant species, mainly in the genusCorydalis (Yan Hu Suo),[1][2] but also in other plants such asStephania rotunda.[3] These plants have traditional uses inChinese herbal medicine. The pharmaceutical industry has synthetically produced the more potentenantiomerLevo-tetrahydropalmatine (Levo-THP; technicallyl-THP, often written L-THP), which has been marketed worldwide under different brand names as an alternative toanxiolytic andsedative drugs of thebenzodiazepine group andanalgesics such asopiates. It is also sold as adietary supplement.
In 1940, aVietnamese scientist Sang Dinh Bui extracted analkaloid from the root ofStephania rotunda with the yield of 1.2–1.5% and he named this compoundrotundin. From 1950 to 1952, two Indian scientists studied and extracted fromStephania glabra anotheralkaloid namedhyndanrine. In 1965, the structure of rotundine and hyndarin was proved to be the same as tetrahydropalmatine.[4]
Tetrahydropalmatine has been demonstrated to possess analgesic effects and may be beneficial in the treatment ofheart disease andliver damage.[5][6] It is a blocker of voltage-activated L-type calcium channel active potassium channels.[citation needed] It is a potent muscle relaxant.[citation needed] It is widely used in China as a sedative.[7]
It has also shown potential in the treatment ofdrug addiction to bothcocaine andopiates, and preliminary human studies have shown promising results.[8][9][10] In animal models, anti-addiction effects can manifest at sub-sedative doses.[7]
In November 2013, the ChineseNational Medical Products Administration issued an order asking for all medications containingl-THP to have their package inserts revised, prohibiting use in pregnant women and those with extrapyramidal disorders, requiring warnings about liver impairement and operation of machinery, and highlighting risks of drowsiness and extrapyramidal symptoms with overuse or when combined with other CNS depressants. Long-term is not advised. The same order lists the following OTC medications as containingl-THP:[11]
| Native name | Translated name | Composition | Indication / Purpose | Package Insert Ref |
|---|---|---|---|---|
| 复方枣仁胶囊 | Compound date seed capsule | Sour-date seeds,l-THP 60 mg | Insomnia. | [12] |
| 罗通定片 | Rotundine tablet | Rotundine 30 mg | Analgesia, sedative-hypnotic. | [13] |
| 盐酸罗通定片 | Rotundine HCl tablet | Rotundine HCl 30 mg | Analgesia, sedative-hypnotic. | [14] |
| 复方维生素U胶囊 | Compoundvitamin U capsule | Al(OH)3 90mg,Mg2Si3O8 72.5mg, "vitamin U" 25mg, licorice extract powder 16.5mg, rotundine 2mg,Bletilla striata 17mg, amylase 25mg, bile powder 1.5mg, menthol 0.5mg | Chronic gastritis, hyperacidity (pain, heartburn, GERD) | [15] |
The pharmacological profile ofl-THP includes antagonism of dopamine D1, and D2 receptors as well as actions at dopamine D3, alpha adrenergic and serotonin receptors. The Ki values forl-THP at D1 and D2 dopamine receptors are approximately 124 nM (D1) and 388 nM (D2). In addition to the antagonism of post-synaptic dopamine receptors, the blockade of pre-synaptic autoreceptors byl-THP results in increased dopamine release, and it has been suggested that lower affinity ofl-THP for D2 receptors may confer some degree of autoreceptor selectivity. Along with dopamine receptors,l-THP has been reported to interact with a number of other receptor types, including alpha-1 adrenergic receptors, at which it functions as an antagonist, and GABA-A receptors, through positive allosteric modulation. Additionally,l-THP displays significant binding to 5-HT1A and alpha-2 adrenergic receptors. In the case of 5-HT1A receptors,l-THP binds with a Ki of approximately 340 nM.[7]
| Target | Organism | Type | Affinity (nM) |
|---|---|---|---|
| F3 | Human | IC50 | 23[16] |
| RT | HIV-1 | IC50 | 562000[16] |
| D1/1A | Human | IC50 | 1630[16] 166±8[7] |
| D1/1A | Human | Ki | 231[16] 124±6[7] |
| D2 | Human | IC50 | 450[16] 1470±270[7] |
| D2 | Human | Ki | 1130[16] >5000[16] 388±78[7] |
| D3 | Human | IC50 | 3250±540[7] |
| D3 | Human | Ki | 1370[16] 1420±220[7] |
| D4 | Human | Ki | >1000[16] |
| D5/1B | Human | Ki | 305[16] |
| 5-HT1A | Human | IC50 | 374±69[7] |
| 5-HT1A | Human | Ki | >5000[16] 340±63[7] |
| α1 | Human | (> 50% inhibition non-selective binding @ 10 μM)[7] | |
| α2 | Human | (> 50% inhibition binding @ 10 μM)6 | |
Animal experiments have shown that the sedative effect of THP results from blockingdopaminergic neurons in thebrain.Dopamine is an importantneurotransmitter in thecentral nervous system where it occurs in several important signaling systems that regulate muscular activity and attention, as well as feelings of joy, enthusiasm, and creativity. Therefore, THP causes no feelings ofeuphoria, and has been seen as an alternative toaddictive drugs for people suffering from anxiety and pain, and as a possibility for relief for people not helped by existing drugs.[citation needed]
L-THP has a pharmacokinetic profile that is favorable for clinical use. L-THP has a long-standing record of safe use in China for a number of indications under the trade-name Rotundine. Concerns about liver toxicity and sedation associated with the use of some l-THP containing herbal preparations in the US are likely due to poor quality and improper use of these unregulated products.[17]
TheUniversity of Maryland has completed a phase I study for THP in people with a history of cocaine use. Their phase II study for cocaine use disorder was withdrawn due to a lack of funding.[18]
l-THP does not improve psychiatric symptoms when added on top ofantipsychotics in schizophrenia.[19]
L-THP has a pharmacokinetic profile that is favorable for clinical x