TETRAHYDROPALMATINE HYDROCHLORIDE

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H25NO4.ClH
Molecular Weight	391.888
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure of TETRAHYDROPALMATINE HYDROCHLORIDE

Structure Search

SMILES

Cl.[H][C@@]12CC3=C(CN1CCC4=CC(OC)=C(OC)C=C24)C(OC)=C(OC)C=C3

InChI

InChIKey=MGSZZQQRTPWMEI-LMOVPXPDSA-N

InChI=1S/C21H25NO4.ClH/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;1H/t17-;/m0./s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17361394 | https://www.ncbi.nlm.nih.gov/pubmed/22300097 | https://www.ncbi.nlm.nih.gov/pubmed/27363313 | Zhang, X. (2017) The Effects of L-Tetrahydropalmatine and Rhynchophylline, Alkaloids Derived from Herbal Medicines, on Cellular and Molecular Neurotoxicity of Cocaine in Pc12 Cells, page 21, retrieved from: https://books.google.ru/books?id=KetSAQAACAAJ

Tetrahydropalmatine is a tetrahydroprotoberberine isoquinoline alkaloid that is a primary active constituent of herbal preparations containing plant species of the genera Stephania and Corydalis. The levo isomer of THP (L-THP) appears to contribute to many of the therapeutic effects of these preparations. The pharmacological profile of L-THP, which includes antagonism of dopamine D1 and D2 receptors and actions at dopamine D3, suggests that it may have utility for treating addiction. Clinical trials where L-THP was used for the treatment of cocaine and heroin addiction have promising results. The clinical trial is planned for the treatment of schizophrenia. L-Tetrahydropalmatine is recorded in the Chinese pharmacopoeia.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Apoptosis 155 Target ID: WP254 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28721806	Activator 1430
Dopamine D1 receptor 101 Target ID: CHEMBL2056 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17361394 \| https://www.ncbi.nlm.nih.gov/pubmed/22300097	Antagonist 2778	124.0 nM [Ki]
Dopamine D2 receptor 297 Target ID: CHEMBL217 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17361394 \| https://www.ncbi.nlm.nih.gov/pubmed/22300097	Antagonist 2778	388.0 nM [Ki]
Dopamine D3 receptor 91 Target ID: CHEMBL3138 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17361394 \| https://www.ncbi.nlm.nih.gov/pubmed/22300097	Binding Agent 1064	1.4 µM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
Schizophrenia 298 Sources: https://clinicaltrials.gov/ct2/show/NCT02118610	Primary	Phase II 1132	Unknown Approved Use Unknown
Cocaine use disorder 5 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22300097 https://www.ncbi.nlm.nih.gov/pubmed/27363313	Primary	Phase II 1132	Unknown Approved Use Unknown
Heroin dependence 10 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22300097 https://www.ncbi.nlm.nih.gov/pubmed/18565275	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
42.8 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27363313	30 mg 2 times / day multiple, oral dose: 30 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TETRAHYDROPALMATINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
396.1 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27363313	30 mg 2 times / day multiple, oral dose: 30 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TETRAHYDROPALMATINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
13.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27363313	30 mg 2 times / day multiple, oral dose: 30 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TETRAHYDROPALMATINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
30 mg 2 times / day multiple, oral Studied dose Dose: 30 mg, 2 times / day Route: oral Route: multiple Dose: 30 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27363313 Page: p.7, 8	healthy, ADULT n = 11 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 11 Sources: https://pubmed.ncbi.nlm.nih.gov/27363313 Page: p.7, 8	Sources: https://pubmed.ncbi.nlm.nih.gov/27363313 Page: p.7, 8

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C8 911 CYP1A2 1524 CYP2C19 1478 MATE1 306 MRP1 106 CYP3A4/5 278 CYP2A6 707 CYP2E1 882 OCT2 647 BCRP 699 P-gp 1461	CYP1A2 1054 CYP3A4/5 85 P-gp 1537

Drug as perpetrator

Target	Modality	Activity
MATE1 308	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32389634/	moderate [IC50 20.9 uM]
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22900779/	no
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22900779/ \| https://pubmed.ncbi.nlm.nih.gov/23001793/	no
CYP2A6 739	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22900779/ \| https://pubmed.ncbi.nlm.nih.gov/23001793/	no
CYP2C19 1553	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22900779/ \| https://pubmed.ncbi.nlm.nih.gov/23001793/	no
CYP2C8 965	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22900779/ \| https://pubmed.ncbi.nlm.nih.gov/23001793/	no
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22900779/ \| https://pubmed.ncbi.nlm.nih.gov/23001793/	no
CYP2E1 970	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22900779/ \| https://pubmed.ncbi.nlm.nih.gov/23001793/	no
CYP3A4/5 335	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22900779/ \| https://pubmed.ncbi.nlm.nih.gov/23001793/	no
MRP1 172	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22900779/	no
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22900779/	weak [IC50 48.6 uM]
OCT2 648	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32389634/	yes [IC50 2.65 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23001793/	yes [Ki 6.42 uM]

Drug as victim

Target	Modality	Activity
P-gp 1537	substrate 3367 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=174006929	no
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23001793/	yes
CYP3A4/5 85	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23001793/	yes

PubMed

Title	Date	PubMed
Evaluation of natural products as inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase.	1991 Jan-Feb	1710653
DL-tetrahydropalmatine-produced hypotension and bradycardia in rats through the inhibition of central nervous dopaminergic mechanisms.	1995 Oct	8577817
DL-Tetrahydropalmatine may act through inhibition of amygdaloid release of dopamine to inhibit an epileptic attack in rats.	2001 Jul 20	11438389
Positive cooperation of protoberberine type 2 alkaloids from Corydalis cava on the GABA(A) binding site.	2003 Apr	12709895
[Effects of L-tetrahydropalmatine on concentrations of neurotransmitter amino acids in mice with cerebral ischemia].	2004 Apr	15706881
[Resource investigation and quality evaluation on wild Corydalis yanhusuo].	2004 May	15706885
[Stereoselective pharmacokinetics of tetrahydropalmatine in rats].	2005 Aug	16268511
A multidisciplinary approach to the toxicologic problems associated with the use of herbal medicines.	2005 Feb	15665747
[Chemical constituents from Corydalis humosa].	2005 Jul	16252721
[Effect of l-tetrahydropalmatine on expression of adhesion molecules induced by lipopolysaccharides in human umbilical vein endothelium cell].	2005 Jun	16110873
Stereoselective pharmacokinetics of tetrahydropalmatine after oral administration of (-)-enantiomer and the racemate.	2005 May 15	15846827
[Studies on the alkaloids from herb of Corydalis adunca].	2005 Nov	16468373
Chiral liquid chromatography resolution and stereoselective pharmacokinetic study of tetrahydropalmatine enantiomers in dogs.	2005 Nov 5	16165405
Liquid chromatography-tandem mass spectrometry for the identification of L-tetrahydropalmatine metabolites in Penicillium janthinellum and rats.	2006 Jan	15959869
[Protective effect of dl-tetrahydropalmatine on liver injury induced by carbon tetrachloride in mice].	2006 Mar	16722379
Large-scale separation of alkaloids from Corydalis decumbens by pH-zone-refining counter-current chromatography.	2006 May 19	16620861
Characterization of enantioselective binding of racemic natural tetrahydropalmatine to DNA by chromatographic methods.	2007 Jan 1	16931189
[Effects of rotundine injection on nitric oxide synthase in tissues of different organs after ischemia/reperfusion of brain in rats].	2007 Jun	17577446
Molecular cloning and characterization of tetrahydroprotoberberine cis-N-methyltransferase, an enzyme involved in alkaloid biosynthesis in opium poppy.	2007 May 18	17389594
Antimalarial activity of alkaloids isolated from Stephania rotunda.	2007 May 30	17382502
[Optimal extraction of Dingxiang jiangqi granules].	2007 Nov	18309666
Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: experiments with self-administration and brain-stimulation reward in rats.	2007 Nov	17888459
Determination of tetrandrine and fangchinoline in plasma samples using hollow fiber liquid-phase microextraction combined with high-performance liquid chromatography.	2007 Sep 14	17675049
Comparative studies on pharmacokinetic fates of tetrahydropalmatine enantiomers in different chemical environments in rats.	2008 Feb	18074336
Simultaneous determination of berberine, palmatine and jatrorrhizine by liquid chromatography-tandem mass spectrometry in rat plasma and its application in a pharmacokinetic study after oral administration of coptis-evodia herb couple.	2008 Mar 1	18258496
One-step purification of palmatine and its derivative dl-tetrahydropalmatine from Enantia chlorantha using high-performance displacement chromatography.	2008 Oct 24	18804774
Cytotoxic activity of alkaloids isolated from Stephania rotunda [corrected].	2009 Apr	19107844
Phytochemicals from Flemingia vestita (Fabaceae) and Stephania glabra (Menispermeaceae) alter cGMP concentration in the cestode Raillietina echinobothrida.	2009 Apr	18854226
[Chemical constituents from Corydalis yanhusuo].	2009 Aug	19894534
[Comparison of microwave-assisted and conventional extraction of Corydalis yanhusuo].	2009 Jul	19873742
Levo-tetrahydropalmatine attenuates cocaine self-administration under a progressive-ratio schedule and cocaine discrimination in rats.	2010 Dec	20816889
Protective effects of tetrahydropalmatine against gamma-radiation induced damage to human endothelial cells.	2010 Jul 3	20562023
Stereoselective protein binding of tetrahydropalmatine enantiomers in human plasma, HSA, and AGP, but not in rat plasma.	2010 Jun	19927376
Combined comparative and chemical proteomics on the mechanisms of levo-tetrahydropalmatine-induced antinociception in the formalin test.	2010 Jun 4	20359166
Screening of antinociceptive components in Corydalis yanhusuo W.T. Wang by comprehensive two-dimensional liquid chromatography/tandem mass spectrometry.	2010 Mar	20101504
Correlation between synergistic action of Radix Angelica dahurica extracts on analgesic effects of Corydalis alkaloid and plasma concentration of dl-THP.	2010 May 4	20307640
Chemical fingerprint analysis of Phellodendri Amurensis Cortex by ultra performance LC/Q-TOF-MS methods combined with chemometrics.	2010 Nov	21049522
Organic cation transporter 1 mediates the uptake of monocrotaline and plays an important role in its hepatotoxicity.	2013 Sep 15	23831208

Patents

Sample Use Guides

In Vivo Use Guide

30 mg twice daily (7 total doses)

Route of Administration: Oral

In Vitro Use Guide

Co-incubation with L-THP (0.01-1ug/ml) did not produce significant effects on 500 uM cocaine-inhibited neurite growth in PC12 cells either at low or high doses.

Name

Type

Language

TETRAHYDROPALMATINE HYDROCHLORIDE

Common Name

English

13A.ALPHA.-BERBINE, 2,3,9,10-TETRAMETHOXY-, HYDROCHLORIDE

Common Name

English

GINDARINE HYDROCHLORIDE

Common Name

English

Tetrahydropalmatine hydrochloride [WHO-DD]

Common Name

English

6H-DIBENZO(A,G)QUINOLIZINE, 5,8,13,13A-TETRAHYDRO-2,3,9,10-TETRAMETHOXY-, HYDROCHLORIDE (1:1), (13AS)-

Systematic Name

English

TETRAHYDROPALMATINE L-FORM HYDROCHLORIDE [MI]

Common Name

English

NSC-36363

Code

English

Code System Code Type Description

PUBCHEM

5351528