Tetrahydropalmatine
Tetrahydropalmatine (THP), also known as rotundine, is a tetrahydroprotoberberine isoquinoline alkaloid with the molecular formula C₂₁H₂₅NO₄ and PubChem CID 5417, characterized by four methoxy groups at positions 2, 3, 9, and 10 on its structure.[1][2] This naturally occurring compound is soluble in chloroform, benzene, ether, and hot ethanol; sparingly soluble in water, but insoluble in other highly polar solvents, and it features a single chiral center that influences its stereoselective metabolism.[1] Primarily extracted from plants in the Papaveraceae family, such as Corydalis yanhusuo (Yan Hu Suo), and the Menispermaceae family, including Stephania epigaea, THP has been widely utilized in traditional Chinese and Southeast Asian medicines for its sedative, analgesic, and anti-inflammatory properties.[1] THP exhibits a broad range of pharmacological activities, including anti-addiction effects, analgesic potential for neuropathic and cancer pain, anti-inflammatory actions, neuroprotective benefits, and emerging anticancer properties.[1] THP has been utilized in traditional medicines and shows promise in clinical trials for conditions like addiction and pain, though it lacks widespread regulatory approval outside certain regions as of 2025.[1][3][4] Pharmacokinetically, THP shows poor intestinal absorption and low oral bioavailability, with a rapid time to maximum concentration (T_max of 0.44 hours) and half-life (T_{1/2} of 4.49 hours) in rats.[1] It undergoes stereoselective metabolism primarily in the liver. Toxicologically, THP has potential for cardiac and neurological adverse effects, though comprehensive studies on acute and long-term toxicity remain limited, indicating a generally safe profile at therapeutic doses but warranting further investigation.[1] As of 2025, ongoing research continues to explore its applications in pain management and addiction treatment.[5][6]Chemistry
Structure and Nomenclature
Tetrahydropalmatine is a tetrahydroprotoberberine alkaloid characterized by the molecular formula \ce{C21H25NO4} and a molar mass of 355.43 g/mol.[7] Its core structure consists of a protoberberine skeleton, a tetracyclic system comprising two aromatic benzene rings (rings A and D) fused to a central isoquinoline (ring B) and a partially saturated piperidine ring (ring C), with tetrahydro substitution at positions 5,8,13, and 13a rendering rings B and C non-aromatic.[7] This arrangement includes a bridged nitrogen atom at position 5, forming the characteristic quinolizidine moiety, along with ether functional groups: four methoxy (-\ce{OCH3}) substituents at positions 2 and 3 on ring A and positions 9 and 10 on ring D.[8] The compound exhibits stereochemistry due to a chiral center at carbon 13a in the saturated ring system. The naturally occurring enantiomer, levo-tetrahydropalmatine (l-THP or (-)-tetrahydropalmatine), possesses the (13aS) configuration and is the biologically active form found in plants.[9] The other enantiomer, dextro-tetrahydropalmatine (d-THP or (+)-tetrahydropalmatine), has reduced pharmacological activity compared to the levo form, highlighting the stereospecificity of the molecule's interaction with biological targets.[10] The systematic IUPAC name for l-THP is (13aS)-5,8,13,13a-tetrahydro-2,3,9,10-tetramethoxy-6H-dibenzo[a,g]quinolizine, reflecting the fused dibenzoquinolizine framework and the specific substitution pattern.[9] Key structural features unique to its protoberberine alkaloid class include the tertiary amine nitrogen bridging rings B and C, which imparts basicity, and the ortho-dimethoxy arrangements on the aromatic rings, contributing to its lipophilicity and potential for hydrogen bonding interactions.[7]Physical and Chemical Properties
Tetrahydropalmatine appears as a white to off-white or pale yellow crystalline solid.[11][12] It typically exists in powder form, which is suitable for pharmaceutical and analytical applications.[13] The compound has a melting point ranging from 145°C to 155°C, depending on the stereoisomer and purity; for example, the racemic form melts at approximately 150°C, while the levo-isomer is reported around 155°C.[14][11][12] Its boiling point is estimated at 482.9°C under standard pressure, though it often decomposes before reaching this temperature.[11] Tetrahydropalmatine exhibits low solubility in water, approximately 0.1 mg/mL at room temperature, rendering it poorly water-soluble.[8] It is slightly soluble in ethanol (about 1 mg/mL) and more readily soluble in organic solvents such as chloroform, methanol (with heating and sonication), DMSO (up to 30 mg/mL), and DMF.[13][15] This solubility profile influences its formulation in pharmaceutical preparations, often requiring solubilizing agents.[16] The compound is sensitive to light and oxidation, which can lead to dehydrogenation and formation of degradation products like palmatine, resulting in a yellow discoloration.[17] It demonstrates stability under neutral to mildly acidic pH conditions (pH 3–7) but degrades in strong acidic or basic environments, as well as under UV exposure or in the presence of ferric ions (Fe³⁺).[18] Proper storage in dark, cool conditions is recommended to maintain integrity.[19] Tetrahydropalmatine has a pKa value of approximately 6.53 for its tertiary amine group, which affects its ionization state and solubility in aqueous media at physiological pH.[13] This protonation behavior is key to its chemical reactivity and analytical detection. Spectroscopically, tetrahydropalmatine shows UV absorption at around 281 nm, useful for quantitative assays.[14] In ¹H NMR, key aromatic protons appear in the 6.5–7.5 ppm range, while aliphatic protons are observed between 2.5–3.5 ppm in CDCl₃ solvent, aiding structural confirmation.[20] These properties facilitate identification and purity assessment in chemical analysis.[21]Sources and History
Natural Occurrence
Tetrahydropalmatine is an isoquinoline alkaloid primarily occurring in plants of the genus Corydalis, particularly Corydalis yanhusuo (also known as Yan Hu Suo in traditional Chinese medicine), where it is one of the major bioactive components in the rhizomes and tubers. It is also found in species of the genus Stephania, such as Stephania rotunda, Stephania epigaea, and Stephania venosa, as well as in trace amounts in other members of the Papaveraceae family, including Corydalis decumbens and Corydalis solida. These plants are predominantly native to East Asia, with major distribution in China and Southeast Asian countries, where C. yanhusuo grows in mountainous regions and is harvested for its medicinal rhizomes.[1][2][22] The content of tetrahydropalmatine varies significantly across plant parts and species, with higher concentrations typically observed in roots and rhizomes compared to aerial parts. In C. yanhusuo, tetrahydropalmatine levels in dry rhizomes range from 0.03% to 0.2% by weight, influenced by geographical origin, cultivation conditions, and processing methods; for instance, samples from Zhejiang Province (a key production area) often exhibit higher quality and content meeting or exceeding the Chinese Pharmacopoeia minimum of 0.04%. In S. rotunda tubers, concentrations can reach up to 3.6% of dry weight, making it a notable source, though variability arises from factors like soil composition, harvest time, and environmental stress. These variations underscore the importance of standardized cultivation for consistent alkaloid yields.[23][24][22] Biosynthetically, tetrahydropalmatine is derived from the amino acid tyrosine through a series of enzymatic steps in the benzylisoquinoline alkaloid (BIA) pathway common to Papaveraceae and Menispermaceae families. Tyrosine undergoes decarboxylation to form tyramine and dopamine, which condense with 4-hydroxyphenylacetaldehyde to yield (S)-norcoclaurine, catalyzed by norcoclaurine synthase (NCS). Subsequent modifications, including O-methylation by norcoclaurine 6-O-methyltransferase (6OMT) and N-methylation, lead to (S)-coclaurine and then reticuline via cytochrome P450 enzymes like CYP80B1. Reticuline undergoes Pictet-Spengler cyclization to form the protoberberine skeleton (scoulerine), followed by additional methylations (e.g., by scoulerine 9-O-methyltransferase, S9OMT) and stereospecific reductions to produce (S)-tetrahydropalmatine. Key enzymes such as NCS and O-methyltransferases are upregulated in high-producing tissues like rhizomes.[25][26][27] Extraction of tetrahydropalmatine from natural sources typically involves solvent-based methods applied to dried rhizomes or tubers, starting with pulverization followed by maceration or reflux in organic solvents like methanol, ethanol, or chloroform to yield crude alkaloid extracts. Yields from C. yanhusuo rhizomes range from 0.1% to 0.5% depending on the technique, with purification achieved through acid-base partitioning, column chromatography, or advanced methods such as high-speed counter-current chromatography (HSCCC) and ultrasonic-assisted aqueous two-phase extraction for improved efficiency and purity above 95%. These processes are optimized to minimize degradation of the alkaloid while maximizing recovery from plant material.[1][28]Discovery and Development
The compound, known as rotundine, was first isolated in 1940 from the roots of Stephania rotunda by Vietnamese scientist Bùi Dinh Sang.[29] In 1962, researchers B. Hsu and K.C. Kin isolated the levo enantiomer (l-THP) from the rhizomes of Corydalis yanhusuo, a plant used in traditional Chinese medicine (TCM), and conducted the initial pharmacological characterization of the compound as a central depressant with sedative and analgesic properties.[30] Concurrently, in China during the 1950s and 1960s, scientists at the Shanghai Institute of Materia Medica, including neuropharmacologist Jin Guozhang, investigated the alkaloids of C. yanhusuo and identified tetrahydropalmatine—named rotundine in Chinese contexts—as a key active component responsible for the plant's pain-relieving effects in TCM formulations. The structure of rotundine was confirmed to be identical to tetrahydropalmatine in 1965 through chemical analysis by M. Kawanishi and S. Sugasawa.[31] The levo enantiomer, l-THP (also known as rotundine), was obtained via resolution of the racemic DL-THP between 1959 and 1964, enabling its synthetic production and clinical evaluation.[30] l-THP received approval from Chinese regulatory authorities in 1964 as a sedative and analgesic agent and was officially listed in the Pharmacopoeia of the People's Republic of China in 1977 under the trade name Rotundine, where it has since been prescribed for conditions including pain, sedation, and muscle relaxation. Outside China, THP is not approved as a pharmaceutical but is available globally as a dietary supplement or research chemical, often derived from natural sources like Corydalis species. Development for addiction treatment accelerated in the 2000s, with a landmark 2008 pilot clinical study in China demonstrating that l-THP reduced opiate craving and increased abstinence rates among heroin-dependent patients during protracted abstinence. In the United States, efforts to pursue FDA Investigational New Drug (IND) status for l-THP in addiction therapy began around 2011, supported by NIH funding, leading to a Phase I trial initiated in 2012 to evaluate its pharmacokinetics and safety in cocaine users, followed by a Phase II pilot for cocaine use disorder starting in 2014.[32][33] These milestones highlight l-THP's transition from TCM-derived alkaloid to a candidate for modern pharmacotherapy, particularly in substance use disorders.Pharmacology
Pharmacokinetics
Tetrahydropalmatine (THP), particularly its levo enantiomer (l-THP), demonstrates a pharmacokinetic profile marked by rapid absorption but limited oral bioavailability due to extensive first-pass metabolism. In preclinical studies using rats, THP is quickly absorbed from the gastrointestinal tract, achieving peak plasma concentrations (C_max) within 0.5–1.25 hours post-oral administration, with absorption appearing nearly complete based on negligible gastrointestinal residue after 24 hours. In humans, absorption is similarly rapid, with a median time to maximum concentration (T_max) of 1.5 hours following oral dosing of l-THP in healthy volunteers and cocaine users. Oral bioavailability remains low, estimated at 2.5–17.8% in rats and comparably limited in humans due to hepatic presystemic extraction, though formulations like self-microemulsifying drug delivery systems can enhance it by up to 2–3-fold.[34][35][36][8] Following absorption, THP distributes widely throughout the body, readily crossing the blood-brain barrier owing to its lipophilic nature. In rats, brain-to-plasma concentration ratios reach 2–4, with peak brain levels occurring around 0.5 hours post-dosing, supporting its central nervous system effects. The apparent volume of distribution is large, approximately 133 L (or ~1.9 L/kg) in humans, indicating extensive tissue penetration and peripheral distribution. Protein binding to human serum albumin exhibits stereoselectivity, with the levo enantiomer showing lower affinity compared to the dextro form, resulting in overall moderate binding estimated at around 40%.[8][34][36][37] Metabolism of THP occurs primarily in the liver via cytochrome P450 enzymes, with CYP3A4/5 and CYP1A2 as the predominant isoforms in human liver microsomes, alongside involvement of CYP2D6. Key biotransformation pathways include O-demethylation to form mono-desmethyl metabolites and subsequent hydroxylation, followed by conjugation (glucuronidation and sulfation); at least 20 metabolites have been identified in humans, with five major ones exceeding 10% of parent drug levels in plasma. The process is stereoselective, with CYP1A2 preferentially metabolizing l-THP and CYP3A isoforms favoring the (+)-enantiomer, leading to faster clearance of l-THP relative to the racemate in some models. The elimination half-life of l-THP is approximately 11–13 hours in humans, longer than the 1.5–4.5 hours observed in rats.[38][39][40][41][35][36] Excretion of THP is dominated by renal elimination of metabolites, with urinary and fecal routes recovering about 46% of the administered dose over 72 hours in humans, primarily as conjugated desmethyl derivatives. Less than 0.2% of unchanged parent drug appears in urine, and gastrointestinal excretion is negligible (<1%). Clearance in humans is around 76 L/h, reflecting efficient metabolic disposition. Pharmacokinetics can be influenced by stereochemistry, with l-THP exhibiting faster clearance than the racemic mixture due to enantiomer-specific enzyme interactions, and by drug interactions such as CYP3A4 inhibitors (e.g., ketoconazole), which increase systemic exposure by reducing metabolism. Pathological states, like hypertension, may prolong half-life, while co-administration with herbal extracts (e.g., Angelica dahurica) can elevate plasma levels.[38][34][35][41][8]Mechanism of Action
Tetrahydropalmatine (THP), particularly its levo enantiomer (l-THP), primarily exerts its pharmacological effects through antagonism at dopamine receptors. l-THP acts as a full antagonist at D1 and D2 dopamine receptors, with binding affinities of Ki = 124 ± 6 nM at D1 and Ki = 388 ± 78 nM at D2.[9] This selective antagonism blocks dopamine-mediated reward pathways in the mesolimbic system, reducing reinforcement behaviors associated with substances of abuse, but without inducing the catalepsy or extrapyramidal side effects typical of high-affinity D2 antagonists like classical antipsychotics. While primarily described as a full antagonist, some studies suggest partial agonist activity at D1 receptors.[42] l-THP also exhibits lower affinity at D3 receptors (Ki ≈ 1,420 nM), contributing to its modulation of dopamine signaling in addiction-related circuits.[9] Beyond dopamine receptors, l-THP interacts with several other targets, albeit with weaker potency. It functions as a partial agonist at α2-adrenergic receptors, potentially contributing to its sedative and anxiolytic properties through enhanced noradrenergic inhibition.[43] l-THP shows weak binding to serotonin 5-HT1A receptors (Ki ≈ 340 nM), where it may act as a partial agonist, and to GABA-A receptors, with evidence of positive allosteric modulation enhancing inhibitory neurotransmission.[9] Additionally, l-THP inhibits L-type calcium channels in a concentration-dependent manner, with an IC50 of approximately 10.3 μM, which may underlie its muscle relaxant and antiarrhythmic effects by reducing calcium influx in excitable cells. At the signaling level, l-THP's dopamine receptor antagonism reduces cAMP accumulation via D1 receptors (Gs-coupled) and prevents D2-mediated inhibition of adenylyl cyclase, thereby modulating downstream cyclic AMP-dependent pathways involved in reward and locomotion.[9] For neuroprotection, l-THP modulates the PI3K/Akt pathway, inhibiting its phosphorylation to attenuate oxidative stress and apoptosis in neuronal models, such as those of acute lung injury or methamphetamine neurotoxicity.[8] Binding profiles indicate no significant activity at opioid receptors, distinguishing l-THP from traditional analgesics.[9] The stereospecificity of THP is pronounced at dopamine sites, with l-THP demonstrating markedly higher potency compared to the d-enantiomer, which exhibits affinities over an order of magnitude weaker.[44] These affinities are typically derived using the Cheng-Prusoff equation for competitive binding:K_i = \frac{IC_{50}}{1 + \frac{[L]}{K_d}}
where IC_{50} is the half-maximal inhibitory concentration, [L] is the concentration of the radiolabeled ligand, and K_d is the dissociation constant of the ligand-receptor complex; this adjustment accounts for the assay conditions to estimate true equilibrium inhibition constants.[9]