Tetrahydropalmatine
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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 an isoquinoline alkaloid found in several different plant species, mainly in the genus Corydalis (Yan Hu Suo),[1][2] but also in other plants such as Stephania rotunda.[3] These plants have traditional uses in Chinese herbal medicine. The pharmaceutical industry has synthetically produced the more potent enantiomer Levo-tetrahydropalmatine (Levo-THP), which has been marketed worldwide under different brand names as an alternative to anxiolytic and sedative drugs of the benzodiazepine group and analgesics such as opiates. It is also sold as a dietary supplement.
In 1940, a Vietnamese scientist Sang Dinh Bui extracted an alkaloid from the root of Stephania rotunda with the yield of 1.2–1.5% and he named this compound rotundin. From 1950 to 1952, two Indian scientists studied and extracted from Stephania glabra another alkaloid named hyndanrine. In 1965, the structure of rotundine and hyndarin was proved to be the same as tetrahydropalmatine.[4]
Effects
[edit]Tetrahydropalmatine has been demonstrated to possess analgesic effects and may be beneficial in the treatment of heart disease and liver 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 of drug addiction to both cocaine and opiates, and preliminary human studies have shown promising results.[8][9][10] In animal models, anti-addiction effects can manifest at sub-sedative doses.[7]
Adverse effects
[edit]In November 2013, the Chinese National Medical Products Administration issued an order asking for all medications containing l-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 containing l-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 | Compound vitamin 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] |
Mechanism of action
[edit]The pharmacological profile of l-THP includes antagonism of dopamine D1, and D2 receptors as well as actions at dopamine D3, alpha adrenergic and serotonin receptors. The Ki values for l-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 by l-THP results in increased dopamine release, and it has been suggested that lower affinity of l-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 blocking dopaminergic neurons in the brain. Dopamine is an important neurotransmitter in the central 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 of euphoria, and has been seen as an alternative to addictive drugs for people suffering from anxiety and pain, and as a possibility for relief for people not helped by existing drugs.[citation needed]
Cases of poisoning
[edit]Several cases of poisoning related to THP have been reported. These cases involved bradycardia, respiratory depression, and CNS depression. Some cases report hepatitis, acute and chronic. Fatalities started to be reported in 1999 in cases where an overdose of THP had been used in combination with other drugs having analgesic and anti-anxiety effects. All 1999 deaths could be tied to a single THP-based supplement, sold under the name "Jin Bu Huan Anodyne Tablets".[17] Toxicity has been reported in children when taken alone.[18] This product was therefore blacklisted by US and European health authorities. In some other countries, such as Singapore, THP is treated as a controlled substance, and license is required to sell it.[17]
In addition, chronic hepatitis has been reported, caused by THP production in East Asia under conditions that were insufficiently sterile.
Research
[edit]The University 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.[19]
See also
[edit]References
[edit]- ^ Sutin EL, Jacobowitz DM (1991). "Neurochemicals in the dorsal pontine tegmentum". Neurobiology of the Locus Coeruleus. Progress in Brain Research. Vol. 88. pp. 3–14. doi:10.1016/S0079-6123(08)63796-6. ISBN 9780444813947. PMID 1726029.
- ^ Ma ZJ, Li XD, Gu XZ, Cheng LP, Mao SJ (March 2006). "[Effects of different types and standard of processing vinegaron inherent constituents in rhizoma of Corydalis yanhusuo]". Zhongguo Zhong Yao Za Zhi = Zhongguo Zhongyao Zazhi = China Journal of Chinese Materia Medica. 31 (6): 465–7. PMID 16722373.
- ^ Andersson C, Bergarp E, Hedman G (January 1992). "[Sick-listed but active]". Läkartidningen. 89 (5): 281–3. PMID 1738250.
- ^ Do TL (2004). Những cây thuốc và vị thuốc Việt Nam. Hà Nội: Nhà xuất bản Y học. p. 780.
- ^ Wu L, Ling H, Li L, Jiang L, He M (May 2007). "Beneficial effects of the extract from Corydalis yanhusuo in rats with heart failure following myocardial infarction". The Journal of Pharmacy and Pharmacology. 59 (5): 695–701. doi:10.1211/jpp.59.5.0010. PMID 17524235. S2CID 25257859.
- ^ Min Q, Bai YT, Shu SJ, Ren P (March 2006). "[Protective effect of dl-tetrahydropalmatine on liver injury induced by carbon tetrachloride in mice]". Zhongguo Zhong Yao Za Zhi = Zhongguo Zhongyao Zazhi = China Journal of Chinese Materia Medica. 31 (6): 483–4, 521. PMID 16722379.
- ^ a b c d e f g h i j k l Wang JB, Mantsch JR (February 2012). "l-tetrahydropalamatine: a potential new medication for the treatment of cocaine addiction". Future Medicinal Chemistry. 4 (2): 177–86. doi:10.4155/fmc.11.166. PMC 3878639. PMID 22300097.
- ^ Mantsch JR, Li SJ, Risinger R, Awad S, Katz E, Baker DA, Yang Z (July 2007). "Levo-tetrahydropalmatine attenuates cocaine self-administration and cocaine-induced reinstatement in rats". Psychopharmacology. 192 (4): 581–91. doi:10.1007/s00213-007-0754-7. PMID 17361394. S2CID 23651147.
- ^ Chu H, Jin G, Friedman E, Zhen X (June 2008). "Recent development in studies of tetrahydroprotoberberines: mechanism in antinociception and drug addiction". Cellular and Molecular Neurobiology. 28 (4): 491–9. doi:10.1007/s10571-007-9179-4. PMID 17710533. S2CID 32614718.
- ^ Yang Z, Shao YC, Li SJ, Qi JL, Zhang MJ, Hao W, Jin GZ (July 2008). "Medication of l-tetrahydropalmatine significantly ameliorates opiate craving and increases the abstinence rate in heroin users: a pilot study". Acta Pharmacologica Sinica. 29 (7): 781–8. doi:10.1111/j.1745-7254.2008.00817.x. PMC 4535343. PMID 18565275.
- ^ Office of the NMPA. "食品药品监管总局办公厅关于修订含左旋延胡索乙素药品处方药说明书和非处方药说明书范本的通知" [Notice of the General Office of the NMPA on the revision of the package inserts for prescription and over-the-counter drugs containing levorotatory tetrahydropalmatine].
- ^ "复方枣仁胶囊(希尔安宁)". ypk.39.net.
- ^ "罗通定片". ypk.39.net.
- ^ "盐酸罗通定片". ypk.familydoctor.com.cn.
- ^ "复方维生素U胶囊(谓泰康)". ypk.39.net.
- ^ a b c d e f g h i j k Liu T. "BindingDB BDBM50424077 (-)-Tetrahydropalmatine::L-Tetrahydropalmatine::TETRAHYDROPALMATINE". bindingdb.org.
- ^ a b Lai CK, Chan AY (February 1999). "Tetrahydropalmatine poisoning: diagnoses of nine adult overdoses based on toxicology screens by HPLC with diode-array detection and gas chromatography-mass spectrometry". Clinical Chemistry. 45 (2): 229–36. doi:10.1093/clinchem/45.2.229. PMID 9931045.
- ^ Centers for Disease Control and Prevention (CDC) (1993). "Jin bu huan toxicity in children--Colorado, 1993". MMWR Morb Mortal Wkly Rep. 42 (33): 633–636. PMID 8350855.
- ^ Kelly D (31 October 2019). "L-tetrahydropalmatine (l-THP) Treatment for Cocaine Use Disorder". clinicaltrials.gov.