Rotundine 483-14-7_Dopamine Receptor_GPCR & G Protein_Signaling Pathways_Products

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.

Physicochemical Properties

Molecular Formula

C21H25NO4

Molecular Weight

355.43

Exact Mass

355.178

CAS #

483-14-7

Related CAS #

Tetrahydropalmatine; 2934-97-6; Tetrahydropalmatine hydrochloride; 6024-85-7

PubChem CID

72301

Appearance

White to off-white solid powder

Density

1.2±0.1 g/cm3

Boiling Point

482.9±45.0 °C at 760 mmHg

Melting Point

141-143ºC

Flash Point

138.7±25.9 °C

Vapour Pressure

0.0±1.2 mmHg at 25°C

Index of Refraction

1.609

LogP

3.7

Hydrogen Bond Donor Count

Hydrogen Bond Acceptor Count

Rotatable Bond Count

Heavy Atom Count

Complexity

475

Defined Atom Stereocenter Count

SMILES

COC1=C(C2=C(C[C@H]3C4=CC(=C(C=C4CCN3C2)OC)OC)C=C1)OC

InChi Key

AEQDJSLRWYMAQI-KRWDZBQOSA-N

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

Chemical Name

(13aS)-2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline

Synonyms

(-)-Tetrahydropalmatine; L-Tetrahydropalmatine; Rotundine

HS Tariff Code

2934.99.9001

Storage

Powder-20°C 3 years

4°C 2 years

In solvent -80°C 6 months

-20°C 1 month

Shipping Condition

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets

D₁ Receptor ( IC50 = 166 nM ); D₂ Receptor ( IC50 = 1400 nM ); D₃ Receptor ( IC50 = 3300 nM ); 5-HT_1A Receptor ( IC50 = 370 nM )

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]

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]

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.

References

[1]. Future Med Chem . 2012 Feb;4(2):177-86.

[2]. J Pharmacol Exp TherActa Pharmacol Sin . 2005 May;26(5):533-8.

[3]. Biol Pharm Bull . 2005 Jan;28(1):176-80.

[4]. Neuropharmacology . 2007 Nov;53(6):771-82.

[5]. Lett Drug Des Discov, 2011, 8(5), 464-468.

Additional Infomation

Tetrahydropalmatine is a berberine alkaloid obtained by formal addition of two molecules of hydrogen to the pyridine ring of palmatine. It has a role as an adrenergic agent, a non-narcotic analgesic and a dopaminergic antagonist. It is a berberine alkaloid, an organic heterotetracyclic compound and an an (S)-7,8,13,14-tetrahydroprotoberberine. It is functionally related to a palmatine.
Tetrahydropalmatine is under investigation in clinical trial NCT02118610 (Treatment of Schizophrenia With L-tetrahydropalmatine (l-THP): a Novel Dopamine Antagonist With Anti-inflammatory and Antiprotozoal Activity).
Tetrahydropalmatine has been reported in Corydalis solida, Fibraurea recisa, and other organisms with data available.

Solubility Data

Solubility (In Vitro)

DMSO: ~8 mg/mL (~22.5 mM)

Water: <1 mg/mL

Ethanol: <1 mg/mL

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
(e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).
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)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL 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).
Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

(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.

PeptideDB

Rotundine 483-14-7

CAS No.: 483-14-7

Physicochemical Properties

Biological Activity

Solubility Data