Tetrahydropalmatine
[CAS# 10097-84-4]

Identification

• Classification: API >> Antipyretic analgesics >> Analgesics
• Name: Tetrahydropalmatine
• Synonyms: Rotundine; 5,8,13,13a-Tetrahydro-2,3,9,10-tetramethoxy-6H-dibenzo[a,g] quinolizine
• Molecular Formula: C₂₁H₂₅NO₄
• Molecular Weight: 355.43
• CAS Registry Number: 10097-84-4
• EC Number: 884-574-5
• SMILES: COC1=C(C2=C(CC3C4=CC(=C(C=C4CCN3C2)OC)OC)C=C1)OC

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*
• Boiling point: 482.9±45.0 °C 760 mmHg (Calc.)^*
• Flash point: 138.7±25.9 °C (Calc.)^*
• Solubility: 10 mM (DMSO) (Expl.)
• Index of refraction: 1.609 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS06 Danger
• Risk Statements: H300
• Safety Statements: P264-P270-P301+P316-P321-P330-P405-P501

Discovery and Applications

Tetrahydropalmatine is an isoquinoline alkaloid belonging to the class of tetrahydroprotoberberine compounds. It occurs naturally in several medicinal plants of the family Papaveraceae, particularly in species such as *Corydalis yanhusuo*, *Stephania rotunda*, and *Corydalis ambigua*. These plants have long been used in traditional Chinese medicine for their analgesic and sedative properties. The compound itself was first isolated in the early 20th century during chemical studies aimed at characterizing the bioactive alkaloids responsible for the pharmacological activity of these herbal preparations.

Structurally, tetrahydropalmatine is a derivative of the protoberberine skeleton, with characteristic features of a tetrahydroisoquinoline ring system. The alkaloid is found in two enantiomeric forms, levo-tetrahydropalmatine (L-THP) and dextro-tetrahydropalmatine (D-THP). The enantiomers show distinct pharmacological profiles, with L-THP demonstrating more pronounced sedative and analgesic effects compared to its D-form. This stereoselectivity has been of significant interest in both basic pharmacological research and clinical application.

The primary applications of tetrahydropalmatine are in the fields of analgesia, sedation, and the treatment of drug addiction. In traditional use, herbal preparations containing this compound were employed for pain relief and as a tranquilizer. Modern pharmacological studies have confirmed these properties, showing that tetrahydropalmatine acts as an antagonist of dopamine D₁ and D₂ receptors, as well as modulating other neurotransmitter systems including serotonin and GABA. This receptor profile explains its sedative, anxiolytic, and analgesic effects.

One of the most notable modern applications of tetrahydropalmatine has been in the management of opioid dependence and substance use disorders. L-THP has been investigated for its potential to reduce cravings and withdrawal symptoms in patients with opioid addiction. Preclinical and clinical studies suggest that its action on dopaminergic and glutamatergic systems contributes to reduced drug-seeking behavior. Additionally, L-THP has been studied in the context of cocaine and alcohol use disorders, with evidence supporting its potential therapeutic role.

In terms of analgesia, tetrahydropalmatine has been shown to provide pain relief in both inflammatory and neuropathic pain models. Its mechanism differs from classical opioids, offering an alternative approach to pain management with reduced risk of tolerance and dependence. The dual effects on dopaminergic and serotonergic systems appear to mediate its analgesic properties. These findings have made it a candidate for development as a non-opioid analgesic, although further clinical validation is needed.

Safety studies have generally indicated that L-THP is well tolerated at therapeutic doses, but higher doses can cause adverse effects such as dizziness, fatigue, or gastrointestinal discomfort. Importantly, there is limited evidence of abuse potential compared with many other psychoactive compounds, although careful monitoring remains important in clinical use. The pharmacokinetics of tetrahydropalmatine show rapid absorption and metabolism, with hepatic cytochrome P450 enzymes playing a major role in its biotransformation.

Tetrahydropalmatine continues to be investigated for a broad range of potential applications, including neuroprotection, treatment of insomnia, and adjunctive therapy in psychiatric conditions. Studies in animal models have demonstrated promising effects in reducing anxiety-like behavior and protecting against neurotoxicity. These findings align with its historical use in traditional medicine as a calming and restorative compound.

From discovery in traditional herbal remedies to modern pharmacological exploration, tetrahydropalmatine exemplifies the bridge between natural product chemistry and therapeutic innovation. Its unique receptor interactions, established safety profile in traditional contexts, and emerging clinical applications highlight its continued relevance in medicinal chemistry and drug development.

References

Tian B, Tian M, and Huang S-M (2020) Advances in phytochemical and modern pharmacological research of Rhizoma Corydalis. Pharmaceutical Biology 58 1 265–275 DOI: 10.1080/13880209.2020.1741651

Yang Z, Shao Y, Li S-S, Qi J, Zhang M, and Wen Q (2008) Medication of l-tetrahydropalmatine significantly ameliorates opiate craving and increases the abstinence rate in heroin users: a pilot study. Acta Pharmacologica Sinica 29 7 781–788 DOI: 10.1111/j.1745-7254.2008.00817.x

Hassan H E, Kelly D, Honick M, Shukla S, Ibrahim A, Grady J, Mantsch J R, and Wang J-B (2017) Pharmacokinetics and safety assessment of l-tetrahydropalmatine in cocaine users: a randomized, double-blind, placebo-controlled study. The Journal of Clinical Pharmacology 57 2 151–160 DOI: 10.1002/jcph.789