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CAS 58-46-8

CAS 58-46-8

Chemistry

Chemistry

MARKET PLACE

1 Intermediates

1 Intermediates

Also known as: 58-46-8, Nitoman, 718635-93-9, Rubigen, Tetrabenzaine, Tetrabenzine

Molecular Formula

C₁₉H₂₇NO₃

Molecular Weight

317.4 g/mol

InChI Key

MKJIEFSOBYUXJB-UHFFFAOYSA-N

A drug formerly used as an antipsychotic and treatment of various movement disorders. Tetrabenazine blocks neurotransmitter uptake into adrenergic storage vesicles and has been used as a high affinity label for the vesicle transport system.

1 2D Structure

CAS 58-46-8

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizin-2-one

2.1.2 InChI

InChI=1S/C19H27NO3/c1-12(2)7-14-11-20-6-5-13-8-18(22-3)19(23-4)9-15(13)16(20)10-17(14)21/h8-9,12,14,16H,5-7,10-11H2,1-4H3

2.1.3 InChI Key

MKJIEFSOBYUXJB-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CC(C)CC1CN2CCC3=CC(=C(C=C3C2CC1=O)OC)OC

2.2 Synonyms

2.2.1 MeSH Synonyms

1. Nitoman

2. Xenazine

2.2.2 Depositor-Supplied Synonyms

1. 58-46-8

2. Nitoman

3. 718635-93-9

4. Rubigen

5. Tetrabenzaine

6. Tetrabenzine

7. Tetra Benazin

8. Xenazine

9. Tetrabenazine (racemate)

10. 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1h-pyrido[2,1-a]isoquinolin-2(11bh)-one

11. Tetrabenazine Racemate

12. Ro 1-9569 Racemate

13. Tetrabenazinum

14. Ro 1-9569

15. Tetrabenazinum [inn-latin]

16. Tetrabenazina [inn-spanish]

17. 9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizin-2-one

18. 9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2h-pyrido[2,1-a]isoquinolin-2-one

19. Deutetrabenazine

20. 9,10-dimethoxy-3-(2-methylpropyl)-1h,2h,3h,4h,6h,7h,11bh-pyrido[2,1-a]isoquinolin-2-one

21. Mls003106727

22. Ro 1-9569/12

23. Chembl117785

24. Chebi:64028

25. (-)-tetrabenazine

26. Ro-19569

27. 2-oxo-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bh-benzo[a]quinolizine

28. 9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2h-pyrido[2,1-a]isoquinolin-2-one

29. Nsc-169886

30. Ncgc00160421-01

31. Nsc 169886

32. 1,2,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-2h-benzo[a]quinolizin-2-one

33. 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2h-pyrido[2,1-a]isoquinolin-2-one

34. Dsstox_cid_22614

35. Dsstox_rid_80059

36. Dsstox_gsid_42614

37. 2-oxo-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2h-benzoquinolizine

38. Cas-58-46-8

39. Xenazine (tn)

40. Smr000718664

41. Nitoman (tn)

42. Wln: T B666 Dv Gntt&j E1y1&1 Lo1 Mo1

43. Tetrabenazin

44. Revocon

45. 2-oxo-3-isobutyl-9,2,3,4,6,7-hexahydro-11bh-benzo[a]quinolizine

46. 2-oxo-3-isobutyl-9,3,4,6,7,11.beta.-hexahydro-2h-benzoquinolizine

47. 1,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-2h-benzo[a]quinolizin-2-one

48. 2h-benzo[a]quinolizin-2-one,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-

49. 2h-benzo[a]quinolizin-2-one,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-

50. 2h-benzo(a)quinolizin-2-one, 1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-

51. 2h-benzo[a]quinolizin-2-one, 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-

52. Ro-1-9569

53. Tetrabenazine- Bio-x

54. Nitoman;ro 1-9569

55. Tetrabenazine (jan/inn)

56. Timtec1_002217

57. 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2h-benzo[a]quinolizin-2-one

58. Oprea1_264344

59. Schembl62026

60. Mls001249426

61. Mls001249497

62. Gtpl4834

63. Hy-b0590a

64. Tetrabenazine Related Impurity 2

65. Dtxsid501127442

66. Hms1540e17

67. Hms2966e06

68. Hms3263i14

69. Hms3430f03

70. Hms3884e10

71. Tetrabenazine (nitoman, Xenazine)

72. Act06890

73. Bcp15831

74. Bcp24156

75. Ex-a2361

76. Tox21_111803

77. Tox21_501086

78. Bdbm50017701

79. Mfcd00042740

80. Mfcd11519951

81. Nsc169886

82. Nsc172187

83. S1789

84. Stk678061

85. Akos001681311

86. Akos016347602

87. Tox21_111803_1

88. Ccg-118217

89. Cs-5700

90. Db04844

91. Lp01086

92. Nsc-172187

93. Pb21652

94. Pb25061

95. Pb38735

96. Sb49797

97. Sdccgsbi-0633786.p001

98. Ncgc00160421-02

99. Ncgc00160421-03

100. Ncgc00160421-06

101. Ncgc00261771-01

102. As-35785

103. Bt164463

104. Sy055407

105. Ft-0674921

106. Ft-0700948

107. Ft-0771873

108. Ft-0772314

109. D08575

110. A856325

111. A917912

112. Q413050

113. Sr-01000833864

114. Sr-01000833864-4

115. Brd-a47564106-001-01-8

116. Z1563146114

117. 2-oxo-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7,11b-hexahydro-2h-benzo(a)quinolizine

118. 2h-benzo[a]quinolizin-2-one, 1,3,4,6,7, 11b-hexahydro-3-isobutyl-9,10-dimethoxy-,

119. 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2h-pyrido[2,1-a]isoquinolin-2-one #

120. 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one

121. 3-isobutyl-9-,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2h-benzo[a]quinolizin-2-one

122. Tetrabenazine (3r,11br)-rel-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2h-benzo[a]quinolizin-2-one

2.3 Create Date

2005-03-26

3 Chemical and Physical Properties

Molecular Formula	C₁₉H₂₇NO₃
Molecular Weight	317.4 g/mol
XLogP3	2.9
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	4
Exact Mass	317.19909372 g/mol
Monoisotopic Mass	317.19909372 g/mol
Topological Polar Surface Area	38.8 Å²
Heavy Atom Count	23
Formal Charge	0
Complexity	425
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	2
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Therapeutic Uses

Adrenergic Uptake Inhibitors

National Library of Medicine's Medical Subject Headings. Tetrabenazine. Online file (MeSH, 2018). Available from, as of March 7, 2018: https://meshb.nlm.nih.gov/search

/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Tetrabenazine is included in the database.

NIH/NLM; ClinicalTrials.Gov. Available from, as of March 7, 2018: https://clinicaltrials.gov/

Xenazine is indicated for the treatment of chorea associated with Huntington's disease. /Included in US product label/

NIH; DailyMed. Current Medication Information for Xenazine (Tetrabenazine) Tablet (Updated: September 1, 2017). Available from, as of March 19, 2018: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ac768bab-8afa-4446-bc7f-caeeffec0cda

/EXPL THER/ Since levodopa-induced peak dyskinesias (LIDs) may reflect, in part, a disproportionate phasic release of dopamine from synaptic vesicles, we examined the ability of the vesicular depletor tetrabenazine (TBZ) to reduce LIDs in 10 dyskinetic advanced Parkinson's disease (PD) patients. After basal evaluation, the patients received, through a slow titration, oral TBZ twice a day for six weeks (up to 50 mg daily) before being re-assessed after a challenge with levodopa. The primary outcome measure was the change in the Unified Parkinson's Disease Rating Scale (UPDRS) dyskinesia score (items 32 to 34). TBZ was well tolerated. A clear treatment effect on LIDs emerged (up to 45%, p<0.05). In two patients a little worsening of motor performance necessitated an increase of the antiparkinsonian therapy, which did not worsen peak-dose LIDs. The patients experienced a clear benefit in terms of their quality of life. In this open-label pilot study, orally administered TBZ resulted in objective and subjective improvements in LIDs. Larger pharmacological studies are in progress.

PMID:24125559 Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812731 Brusa L et al; Funct Neurol. 2013 Apr-May;28(2):101-5 (2013)

For more Therapeutic Uses (Complete) data for Tetrabenazine (8 total), please visit the HSDB record page.

4.2 Drug Warning

/BOXED WARNING/ WARNING: DEPRESSION AND SUICIDALITY. Xenazine can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Anyone considering the use of Xenazine must balance the risks of depression and suicidality with the clinical need for control of chorea. Close observation of patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior should accompany therapy. Patients, their caregivers, and families should be informed of the risk of depression and suicidality and should be instructed to report behaviors of concern promptly to the treating physician. Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation, which are increased in frequency in Huntington's disease. Xenazine is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression.

Caution should be exercised in treating patients with tetrabenazine who have a history of depression or prior suicide attempts or ideation since these patients may be at an increased risk for suicidal behavior. Patients who are actively suicidal or those with untreated or inadequately treated depression should not be treated with the drug.

American Society of Health-System Pharmacists 2017; Drug Information 2017. Bethesda, MD. 2017

Huntington's disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. In a 12-week controlled trial, Xenazine was also shown to cause slight worsening in mood, cognition, rigidity, and functional capacity. Whether these effects persist, resolve, or worsen with continued treatment is unknown.

Prior to administering tetrabenazine dosages exceeding 50 mg daily, the manufacturer recommends patients be tested to determine their cytochrome P-450 (CYP) isoenzyme 2D6 status (i.e., poor metabolizers, extensive metabolizers, intermediate metabolizers).1 Drug exposure will be substantially higher (about threefold for alpha-dihydrotetrabenazine (a-HTBZ) and ninefold for beta-dihydrotetrabenazine (beta-HTBZ), both active metabolites) when a dose is given to a poor metabolizer than when given to an extensive metabolizer.1 The manufacturer recommends limiting the dosage of tetrabenazine to 50 mg daily and single doses of the drug to 25 mg in patients who are poor CYP2D6 metabolizers.

American Society of Health-System Pharmacists 2017; Drug Information 2017. Bethesda, MD. 2017

For more Drug Warnings (Complete) data for Tetrabenazine (22 total), please visit the HSDB record page.

4.3 Drug Indication

Treatment of hyperkinetic movement disorders like chorea in Huntington's disease, hemiballismus, senile chorea, Tourette syndrome and other tic disorders, and tardive dyskinesia

FDA Label

5 Pharmacology and Biochemistry

5.1 Pharmacology

Prolongation of the QTc interval has been observed at doses of 50 mg. In rats, it has been observed that tetrabenazine or its metabolites bind to melanin-containing tissues such as the eyes and skin. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing.

5.2 MeSH Pharmacological Classification

Adrenergic Uptake Inhibitors

Drugs that block the transport of adrenergic transmitters into axon terminals or into storage vesicles within terminals. The tricyclic antidepressants (ANTIDEPRESSIVE AGENTS, TRICYCLIC) and amphetamines are among the therapeutically important drugs that may act via inhibition of adrenergic transport. Many of these drugs also block transport of serotonin. (See all compounds classified as Adrenergic Uptake Inhibitors.)

5.3 FDA Pharmacological Classification

5.3.1 Pharmacological Classes

Vesicular Monoamine Transporter 2 Inhibitors [MoA]; Vesicular Monoamine Transporter 2 Inhibitor [EPC]

5.4 ATC Code

N - Nervous system

N07 - Other nervous system drugs

N07X - Other nervous system drugs

N07XX - Other nervous system drugs

N07XX06 - Tetrabenazine

N - Nervous system

N07 - Other nervous system drugs

N07X - Other nervous system drugs

N07XX - Other nervous system drugs

N07XX16 - Deutetrabenazine

5.5 Absorption, Distribution and Excretion

Absorption

Route of Elimination

After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated (75%). Tetrabenazine is also cleared fecally (7% to 16%). Unchanged tetrabenazine has not been found in human urine. Urinary excretion of -HTBZ or -HTBZ (the major metabolites) accounted for less than 10% of the administered dose.

Volume of Distribution

Steady State, IV, in HD or tardive dyskinesia patients: 385L. Tetrabenazine is rapidly distributed to the brain following IV injection. The site with the highest binding is the striatum, while the lowest binding was observed in the cortex.

Clearance

IV, 1.67 L/min in HD or tardive dyskinesia patients

The in vitro protein binding of tetrabenazine, alpha-dihydrotetrabenazine (a-HTBZ), and beta-dihydrotetrabenazine (b-HTBZ) was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, a-HTBZ binding ranged from 60% to 68%, and b-HTBZ binding ranged from 59% to 63%.

Results of PET-scan studies in humans show that radioactivity is rapidly distributed to the brain following intravenous injection of (11)C-labeled tetrabenazine or alpha-dihydrotetrabenazine (a-HTBZ), with the highest binding in the striatum and lowest binding in the cortex.

Tetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing.

Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine by carbonyl reductase to the active metabolites alpha-dihydrotetrabenazine (a-HTBZ) and beta-dihydrotetrabenazine (b-HTBZ). a-HTBZ and b-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (Cmax) of a-HTBZ and b-HTBZ are reached within 1 to 1 1/2 hours post-dosing. a-HTBZ is subsequently metabolized to a minor metabolite, 9-desmethyl-a-DHTBZ. b-HTBZ is subsequently metabolized to another major circulating metabolite, 9-desmethyl-b-DHTBZ, for which Cmax is reached approximately 2 hours post-dosing.

5.6 Metabolism/Metabolites

Tetrabenazine is hepatically metabolized. Carbonyl reductase in the liver is responsible for the formation of two major active metabolites: -dihydrotetrabenazine (-HTBZ) and -dihydrotetrabenazine (-HTBZ). -HTBZ is further metabolized into 9-desmethyl--DHTBZ, a minor metabolite by CYP2D6 and with some contribution of CYP1A2. -HTBZ is metabolized to another major circulating metabolite, 9-desmethyl--DHTBZ, by CYP2D6. The Tmax of this metabolite is 2 hours post-administration of tetrabenazine.

In a mass balance study in 6 healthy volunteers, approximately 75% of the dose was excreted in the urine, and fecal recovery accounted for approximately 7 to 16% of the dose. Unchanged tetrabenazine has not been found in human urine. Urinary excretion of alpha-dihydrotetrabenazine (a-HTBZ) or beta-dihydrotetrabenazine (b-HTBZ) accounted for less than 10% of the administered dose. Circulating metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites as well as products of oxidative metabolism, account for the majority of metabolites in the urine.

After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated.

The results of in vitro studies do not suggest that tetrabenazine, alpha-dihydrotetrabenazine (a-HTBZ), beta-dihydrotetrabenazine (b-HTBZ) or 9-desmethyl-beta-dihydrotetrabenazine are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its a- or b-HTBZ or 9-desmethyl-beta-dihydrotetrabenazine metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.

After oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. alpha-Dihydrotetrabenazine (a-HTBZ), beta-dihydrotetrabenazine (b-HTBZ) and 9-desmethyl-beta-dihydrotetrabenazine are the major circulating metabolites and are subsequently metabolized to sulfate or glucuronide conjugates. a-HTBZ and b-HTBZ are formed by carbonyl reductase that occurs mainly in the liver. a-HTBZ is O-dealkylated by CYP450 enzymes, principally CYP2D6, with some contribution of CYP1A2 to form 9-desmethyl-alpha-dihydrotetrabenazine, a minor metabolite. b-HTBZ is O-dealkylated principally by CYP2D6 to form 9-desmethyl-beta-dihydrotetrabenazine.

5.7 Biological Half-Life

-HTBZ = 7 hours; -HTBZ = 5 hours; 9-desmethyl--DHTBZ = 12 hours.

alpha-Dihydrotetrabenazine (a-HTBZ), beta-dihydrotetrabenazine (b-HTBZ) and 9-desmethyl-beta-dihydrotetrabenazine have half-lives of 7 hours, 5 hours and 12 hours respectively. /Tetrabenazine metabolites/

5.8 Mechanism of Action

Tetrabenazine is a reversible human vesicular monoamine transporter type 2 inhibitor (Ki = 100 nM). It acts within the basal ganglia and promotes depletion of monoamine neurotransmitters serotonin, norepinephrine, and dopamine from stores. It also decreases uptake into synaptic vesicles. Dopamine is required for fine motor movement, so the inhibition of its transmission is efficacious for hyperkinetic movement. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM).

... Pharmacology studies demonstrate that betrabenzaine reversibly inhibits the activity of vesicular monoamine transporter 2, resulting in depletion of central dopamine. ...

PMID:22749259 Chen JJ et al; Clin Ther 34 (7): 1487-504 (2012)