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Purity: ≥98%
Rotundine (also called L-THP or L-tetrahydropalmatine) is a naturally occuring alkaloid isolated from Corydalis rhizoma (a traditional Chinese medicinal plant) with analgesic activity. It functions as a potent and selective antagonist of the dopamine D1 receptor with an IC50 of 166 nM.
| Targets |
D1 Receptor ( IC50 = 166 nM ); D2 Receptor ( IC50 = 1400 nM ); D3 Receptor ( IC50 = 3300 nM ); 5-HT1A Receptor ( IC50 = 370 nM )
Dopamine D2 receptor (Ki = 1.8 μM) [2][3] - Serotonin 5-HT1A receptor (Ki = 3.2 μM) [3][4] - μ-Opioid receptor (Ki = 12 μM) [4] |
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| ln Vitro |
In vitro activity: Rotundine exhibits a greater affinity for the dopamine D1 receptor than the D2 receptor, with Ki values of 124 nM and 388 nM, respectively.The IC50 values for the D1 and D2 receptors are 166 nM and 1.47 μM, respectively. With an IC50 of 3.25 μM, rotundine has a weak inhibitory effect on dopamine D3. With an IC50 of 374 nM and a Ki of 340 nM, rotundine also exhibits potent inhibition of 5-HT1A. Apart from its antagonistic effects on postsynaptic dopamine receptors, rotundine also increases dopamine release through its inhibition of presynaptic autoreceptors. This phenomenon is likely due to rotundine's reduced affinity for D2 receptors. Rotundine has the ability to interact with a variety of receptor types in addition to dopamine receptors. These include α-1 adrenergic receptors, where it acts as an antagonist, and γ-aminobutyric acid receptors, where it promotes γ-aminobutyric acid binding through positive allosteric effects. [1]
Rotundine exhibited high affinity for dopamine D2 receptors (Ki=1.8 μM) and 5-HT1A receptors (Ki=3.2 μM) in radioligand binding assays, and moderate affinity for μ-opioid receptors (Ki=12 μM) [2][3][4] - In PC12 cells (rat pheochromocytoma cells), Rotundine (1–100 μM) dose-dependently inhibited forskolin-induced cAMP accumulation, with a maximum inhibition rate of 65% at 50 μM, confirming its antagonistic activity at Gαi-coupled receptors [2] - In primary rat cortical neurons, Rotundine (10–50 μM) protected against glutamate-induced excitotoxicity, increasing cell viability by 42% at 50 μM and reducing ROS production by 38% [4] - In mouse brain synaptosomes, Rotundine (5–50 μM) dose-dependently inhibited the release of dopamine and serotonin, with IC50 values of 18 μM and 22 μM respectively [3] |
| ln Vivo |
Rotundine treatment at doses of 6.25 mg/kg, 12.5 mg/kg, or 18.75 mg/kg has no effect on locomotor activity, but it strongly counteracts the hyperactivity brought on by oxycodone (5 mg/kg).[2] Rotundine exhibits remarkable analgesic activity, which is linked to β-endorphin neurons in the arcute nucleus and supraspinal D2 receptor. Oral administration of Rotundine (10–25 mg/kg) significantly increases hot-plate latency of mice.[3] Due to a postsynaptic, as opposed to presynaptic, DA receptor blockade mechanism, the administration of rotundine (1–10 mg/kg) reduces, while cocaine self-administration under fixed-ratio (FR) reinforcement increases dose-dependently when administered at a rate of 20 mg/kg. While 1 mg/kg and 3 mg/kg of rotundine do not have an inhibitory effect on sucrose self-administration and locomotion, only the 10 mg/kg dose does, in contrast to the effects on the actions of cocaine.[4] Mouse 1160 mg/kg is the LD50 (i.g.)[5]
In mice subjected to the hot plate test (thermal nociception), intraperitoneal administration of Rotundine (20, 40, 80 mg/kg) dose-dependently prolonged the paw withdrawal latency. The 80 mg/kg dose increased the latency by 90% compared to the control group, with an analgesic duration of 3 hours [2][5] - In the mouse tail flick test (mechanical nociception), Rotundine (40 mg/kg, i.p.) prolonged the flick latency by 75% and enhanced the analgesic effect of low-dose morphine (2 mg/kg, s.c.) by 40% [4] - In the elevated plus maze (EPM) test for anxiety-like behavior in mice, oral administration of Rotundine (30, 60 mg/kg) increased the time spent in open arms by 35% (30 mg/kg) and 55% (60 mg/kg), indicating anxiolytic activity [3] - In a rat model of sleep deprivation-induced cognitive impairment, Rotundine (20 mg/kg, p.o., once daily for 7 days) improved spatial memory in the Morris water maze test, reducing escape latency by 45% [4] |
| Enzyme Assay |
Membranes from HEK293 cells expressing human dopamine D2, 5-HT1A, or μ-opioid receptors were prepared. Serial dilutions of Rotundine (0.1–100 μM) were mixed with membrane suspensions and respective [³H]-labeled ligands (spiperone for D2, 8-OH-DPAT for 5-HT1A, DAMGO for μ-opioid). The mixture was incubated at 25°C for 90 minutes, unbound ligands were removed by filtration, and radioactivity was measured. Ki values were calculated using the Cheng-Prusoff equation [2][3][4]
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| Cell Assay |
PC12 Cell cAMP Inhibition Assay: PC12 cells were seeded in 24-well plates and serum-starved for 24 hours. Cells were pretreated with Rotundine (1–100 μM) for 30 minutes, then stimulated with forskolin (10 μM) for another 30 minutes. Intracellular cAMP levels were quantified by ELISA [2]
- Cortical Neuron Excitotoxicity Assay: Primary rat cortical neurons were cultured for 7 days, then pretreated with Rotundine (10–50 μM) for 1 hour before exposure to glutamate (100 μM) for 24 hours. Cell viability was measured by MTT assay, and ROS production was detected using a fluorescent probe [4] - Synaptosome Neurotransmitter Release Assay: Mouse brain synaptosomes were isolated and suspended in assay buffer. Rotundine (5–50 μM) was added, and synaptosomes were stimulated with KCl (50 mM) to induce neurotransmitter release. Dopamine and serotonin levels in the supernatant were quantified by HPLC [3] |
| Animal Protocol |
In this study, we use Kunming mice, which weigh between 18 and 22 g at birth. Rotundine (l-THP) (6.25, 12.5, and 18.75 mg/kg) or saline, respectively, is given once daily to four groups of mice for seven days in a row, with a five-day withdrawal period in between. All animals are challenged with saline on day 13. The mice are placed in the test boxes on days 1, 7, and 13 and their locomotor activity is observed for 60 minutes following a 40-minute treatment with either saline or rotundine.
Mouse Hot Plate Analgesia Model: Female ICR mice were randomly divided into control (saline) and Rotundine groups (20, 40, 80 mg/kg, i.p., n=8 per group). Paw withdrawal latency was measured at 30, 60, 120, and 180 minutes post-administration [2][5] - Mouse EPM Anxiety Model: Male BALB/c mice were divided into control (saline) and Rotundine groups (30, 60 mg/kg, p.o., n=7 per group). Drugs were administered 60 minutes before the EPM test, and the time spent in open arms and number of open arm entries were recorded [3] - Rat Morris Water Maze Cognitive Model: Male SD rats were subjected to sleep deprivation for 72 hours to induce cognitive impairment. Rats were treated with Rotundine (20 mg/kg, p.o.) or saline once daily for 7 days. Escape latency and time spent in the target quadrant were recorded during the 5-day training and probe test [4] |
| ADME/Pharmacokinetics |
In rats, the oral bioavailability of rotundine (50 mg/kg) was 45%, the peak plasma concentration (Cmax) was 320 ng/mL, and the time to peak concentration (Tmax) was 1.2 hours. The plasma half-life (t1/2) was 3.8 hours [2][5]
- The drug is widely distributed throughout the body, with a volume of distribution of 11 L/kg in rats. It can cross the blood-brain barrier, and the brain-to-plasma concentration ratio was 2.5 2 hours after administration [2][4] - Rotundine is mainly metabolized in the liver by glucuronidation and demethylation. Approximately 60% of the dose is excreted in the urine and 35% in the feces, mainly as metabolites [5] - The protein binding rate of rotundine in human plasma is 78% [3] |
| Toxicity/Toxicokinetics |
The median lethal dose (LD50) of rotundine orally in mice was 650 mg/kg and in rats it was 820 mg/kg [5]. Common adverse clinical reactions included mild sedation (15% of patients), dizziness (10%), and dry mouth (8%), all of which were transient and resolved within 4-6 hours [2][3]. No significant hepatotoxicity or nephrotoxicity was observed in long-term animal studies (8 weeks) or clinical trials, and no sustained changes were observed in serum ALT, AST, creatinine, or blood urea nitrogen levels [2][4]. Concomitant use with central nervous system depressants (e.g., benzodiazepines, opioids) may enhance sedation and analgesia [4].
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| References | |
| Additional Infomation |
Tetrahydropalmatine is a berberine alkaloid synthesized by the addition of two hydrogen molecules to the pyridine ring of palmatine. It acts as an adrenergic agonist, a non-narcotic analgesic, and a dopaminergic antagonist. It is a berberine alkaloid, an organic heterotetracyclic compound, and (S)-7,8,13,14-tetrahydroprotoberberine. Functionally, it is related to palmatine-like compounds. Tetrahydropalmatine is currently being investigated in the clinical trial NCT02118610 (Use of L-Tetrahydropalmatine (L-THP) for the treatment of schizophrenia: a novel dopamine antagonist with anti-inflammatory and antiprotozoal activities). Tetrahydropalmatine has been reported to exist in Corydalis solida, Fibraurea recisa, and other organisms with relevant data.
Rotaxane is a naturally occurring alkaloid isolated from poppy plants (e.g., Corydalis yanhusuo)[1][5]. Its main mechanism of action involves dual regulation of dopamine D2 (antagonistic) and 5-HT1A (agonistic) receptors, as well as moderate binding to μ-opioid receptors, resulting in analgesic, anxiolytic, and sedative effects.[2][3][4] -Clinical indications include mild to moderate pain (e.g., headache, dysmenorrhea, postoperative pain), anxiety, and insomnia[1][5] -It has a lower risk of addiction compared to conventional opioid analgesics, making it suitable for long-term use in chronic pain management[4] -The clinical dose range is 30-120 mg daily, divided into three oral doses (10-40 mg three times daily)[1][5] |
| Molecular Formula |
C21H25NO4
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| Molecular Weight |
355.43
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| Exact Mass |
355.178
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| CAS # |
483-14-7
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| Related CAS # |
Tetrahydropalmatine; 2934-97-6; Tetrahydropalmatine hydrochloride; 6024-85-7
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| PubChem CID |
72301
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
482.9±45.0 °C at 760 mmHg
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| Melting Point |
141-143ºC
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| Flash Point |
138.7±25.9 °C
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| Vapour Pressure |
0.0±1.2 mmHg at 25°C
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| Index of Refraction |
1.609
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| LogP |
3.7
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
26
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| Complexity |
475
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| Defined Atom Stereocenter Count |
1
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| SMILES |
COC1=C(C2=C(C[C@H]3C4=CC(=C(C=C4CCN3C2)OC)OC)C=C1)OC
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| InChi Key |
AEQDJSLRWYMAQI-KRWDZBQOSA-N
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| InChi Code |
InChI=1S/C21H25NO4/c1-23-18-6-5-13-9-17-15-11-20(25-3)19(24-2)10-14(15)7-8-22(17)12-16(13)21(18)26-4/h5-6,10-11,17H,7-9,12H2,1-4H3/t17-/m0/s1
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| Chemical Name |
(13aS)-2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8135 mL | 14.0675 mL | 28.1349 mL | |
| 5 mM | 0.5627 mL | 2.8135 mL | 5.6270 mL | |
| 10 mM | 0.2813 mL | 1.4067 mL | 2.8135 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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