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Also known as: Cis-flupentixol, Fluanxol, Cis-(z)-flupenthixol, Flupenthixol, Fluxanxol, Emergil

Molecular Formula

C₂₃H₂₅F₃N₂OS

Molecular Weight

434.5 g/mol

InChI Key

NJMYODHXAKYRHW-DVZOWYKESA-N

FDA UNII

FA0UYH6QUO

A thioxanthene neuroleptic that, unlike CHLORPROMAZINE, is claimed to have CNS-activating properties. It is used in the treatment of psychoses although not in excited or manic patients. (From Martindale, The Extra Pharmacopoeia, 30th ed, p595)

1 2D Structure

Flupenthixol

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-[4-[(3Z)-3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazin-1-yl]ethanol

2.1.2 InChI

InChI=1S/C23H25F3N2OS/c24-23(25,26)17-7-8-22-20(16-17)18(19-4-1-2-6-21(19)30-22)5-3-9-27-10-12-28(13-11-27)14-15-29/h1-2,4-8,16,29H,3,9-15H2/b18-5-

2.1.3 InChI Key

NJMYODHXAKYRHW-DVZOWYKESA-N

2.1.4 Canonical SMILES

C1CN(CCN1CCC=C2C3=CC=CC=C3SC4=C2C=C(C=C4)C(F)(F)F)CCO

2.1.5 Isomeric SMILES

C1CN(CCN1CC/C=C\2/C3=CC=CC=C3SC4=C2C=C(C=C4)C(F)(F)F)CCO

2.2 Other Identifiers

2.2.1 UNII

FA0UYH6QUO

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Alpha-flupenthixol

2. Cis-flupenthixol

3. Emergil

4. Fluanxol

5. Flupenthixol

2.3.2 Depositor-Supplied Synonyms

1. Cis-flupentixol

2. Fluanxol

3. Cis-(z)-flupenthixol

4. Flupenthixol

5. Fluxanxol

6. Emergil

7. Cis-flupenthixol

8. Siplaril

9. Siplarol

10. Alpha-flupenthixol

11. Zuflupentixol

12. 53772-82-0

13. Lc 44

14. Flupenthixole

15. Fa0uyh6quo

16. 2709-56-0

17. Fluphenthixol

18. 2-[4-[(3z)-3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazin-1-yl]ethanol

19. Cis-(z)-flupenthixol Dihydrochloride

20. Chebi:10454

21. N 7009

22. N-7009

23. 4-(3-(2-(trifluoromethyl)-9h-thioxanthen-9-ylidene)propyl)-1-piperazineethanol

24. 4-(3-(2-(trifluoromethyl)thioxanthen-9-ylidene)propyl)-1-piperazineethanol

25. 1-piperazineethanol, 4-(3-(2-(trifluoromethyl)-9h-thioxanthen-9-ylidene)propyl)-

26. 1-piperazineethanol, 4-(3-(2-(trifluoromethyl)-9h-thioxanthen-9-ylidene)propyl)-, (z)-

27. Ncgc00162179-02

28. 1-piperazineethanol, 4-(3-(2-(trifluoromethyl)thioxanthen-9-ylidene)propyl)-

29. Dsstox_cid_26310

30. Dsstox_rid_81531

31. Dsstox_gsid_46310

32. Flupentiol

33. Mls001332581

34. Flupentixolum [inn-latin]

35. (z)-4-(3-(2-(trifluoromethyl)-9h-thioxanthen-9-ylidene)propyl)piperazine-1-ethanol

36. (z)-4-[3-[2-(trifluoromethyl)-9h-thioxanthen-9-ylidene]propyl]piperazine-1-ethanol

37. 1-piperazineethanol, 4-[3-[2-(trifluoromethyl)-9h-thioxanthen-9-ylidene]propyl]-

38. 2-trifluoromethyl-9-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propylidene)thioxanthene

39. 4-[3-[2-(trifluoromethyl)-9h-thioxanthen-9-ylidene]propyl]-1-piperazineethanol

40. Cas-53772-82-0

41. Unii-fa0uyh6quo

42. Smr000875208

43. Einecs 220-304-9

44. Einecs 258-756-4

45. Flupentixolo

46. Flurentixol

47. Flupentixol [inn:ban:dcf]

48. Cis Flupenthixol

49. (z)-flupentixol

50. 1-piperazineethanol, 4-[(3z)-3-[2-(trifluoromethyl)-9h-thioxanthen-9-ylidene]propyl]-

51. 2-trifluoromethyl-9-[3-[4-(2-hydroxyethyl)piperazin-1-yl]propylidene]thioxanthene

52. Cis(z)flupenthixol

53. 1-piperazineethanol, 4-((3z)-3-(2-(trifluoromethyl)-9h-thioxanthen-9-ylidene)propyl)-

54. Depixol (tn)

55. Flupentixol (inn)

56. Z-flupenthixol

57. Z-flupentixol

58. Prestwick2_000340

59. Prestwick3_000340

60. Biomol-nt_000021

61. Flupentixol, (z)-

62. (z)-4-(3-(2-(trifluoromethyl)-9h-thioxanthen-9-ylidene)propyl)-1-piperazineethanol

63. .alpha.-flupenthixol

64. Unii-21hmq851is

65. Lopac0_000528

66. Schembl34200

67. Bspbio_000379

68. Gtpl948

69. Chembl54661

70. 21hmq851is

71. Bpbio1_000417

72. Bpbio1_001183

73. Dtxsid9046310

74. Bdbm79172

75. (z)-2-[4-[3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazin-1-yl]ethanol

76. Cid_10140115

77. Lc-44

78. Tox21_112003

79. Zinc29489118

80. Tox21_112003_1

81. Ccg-204618

82. Db00875

83. Sdccgsbi-0050511.p002

84. Ncgc00162179-01

85. Ncgc00162179-03

86. Ncgc00162179-04

87. Ncgc00162179-05

88. Ncgc00162179-06

89. Ncgc00162179-08

90. Ncgc00162179-12

91. D01044

92. L000972

93. Q420350

94. W-107130

95. Brd-k70487031-001-01-0

96. (z)-2-(4-(3-(2-(trifluoromethyl)-9h-thioxanthen-9-ylidene)propyl)piperazin-1-yl)ethanol

97. 2-(4-(3-[2-(trifluoromethyl)-9h-thioxanthen-9-ylidene]propyl)-1-piperazinyl)ethanol #

98. 2-trifluoromethyl-9-(3-(4-(.beta.-hydroxyethyl)-1-piperazinyl)propylidene)thioxanthene

99. 2-[4-[(3z)-3-[2-(trifluoromethyl)-9-thioxanthenylidene]propyl]-1-piperazinyl]ethanol;hydrochloride

100. 2-[4-[(3z)-3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazino]ethanol;hydrochloride

101. 4-((3z)-3-(2-(trifluoromethyl)-9h-thioxanthen-9-ylidene)propyl)-1-piperazineethanol

2.4 Create Date

2005-03-27

3 Chemical and Physical Properties

Molecular Formula	C₂₃H₂₅F₃N₂OS
Molecular Weight	434.5 g/mol
XLogP3	4.5
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	5
Exact Mass	434.16396908 g/mol
Monoisotopic Mass	434.16396908 g/mol
Topological Polar Surface Area	52 Å²
Heavy Atom Count	30
Formal Charge	0
Complexity	592
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	1
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Flupentixol is indicated for maintenance therapy of chronic schizophrenic patients whose main manifestations do not include excitement, agitation or hyperactivity. It is indicated for the management of depression in adult patients who may, or may not, also be showing signs of anxiety. Flupentixol in combination with [melitracen] is indicated to manage symptoms of anxiety, depression, and asthenia in adults.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Flupentixol is an antipsychotic agent with anxiolytic and mild sedative actions. It exerts weak anticholinergic and adrenergic effects. It possesses antiemetic actions. As flupentixol works by antagonizing dopamine actions, it can cause extrapyramidal effects, mostly at doses greater than 10 mg. In clinical trials, flupentixol-induced extrapyramidal effects have been managed with anti-Parkinsonian drugs. Drug esterification in the intramuscular formulation of the drug results in slow release of the drug from the injection site and a prolonged duration of action. Flupentixol has been investigated for use in mild to moderate depression: compared to other antidepressant agents, flupentixol has a rapid onset of action, where antidepressive effects were observed within the first two to three days after administration. As with other antipsychotic agents, flupentixol can cause QTc prolongation and increase the risk of arrhythmias. In clinical trials, flupentixol was associated with the risk of cardiovascular disease, cerebrovascular adverse events, stroke, and venous thromboembolism. Flupentixol can elevate the levels of prolactin; however, the clinical significance of hyperprolactinemia caused by neuroleptic drugs is unclear. Long-term hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone mineral density in both female and male subjects. Interestingly, recent studies show that flupentixol exhibits anti-tumour properties alone or synergistically with other anticancer drugs like gefitinib. One study demonstrated that _in vitro_, flupentixol docks to the ATP binding pocket of phosphatidylinositol 3-kinase (PI3K), a lipid kinase that activates signalling pathways that are often hyperactivated in some cancers. Flupentixol inhibited the PI3K/AKT pathway and survival of lung cancer cells _in vitro_ and _in vivo_.

5.2 MeSH Pharmacological Classification

Antipsychotic Agents

Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus. (See all compounds classified as Antipsychotic Agents.)

Dopamine Antagonists

Drugs that bind to but do not activate DOPAMINE RECEPTORS, thereby blocking the actions of dopamine or exogenous agonists. Many drugs used in the treatment of psychotic disorders (ANTIPSYCHOTIC AGENTS) are dopamine antagonists, although their therapeutic effects may be due to long-term adjustments of the brain rather than to the acute effects of blocking dopamine receptors. Dopamine antagonists have been used for several other clinical purposes including as ANTIEMETICS, in the treatment of Tourette syndrome, and for hiccup. Dopamine receptor blockade is associated with NEUROLEPTIC MALIGNANT SYNDROME. (See all compounds classified as Dopamine Antagonists.)

5.3 ATC Code

N - Nervous system

N05 - Psycholeptics

N05A - Antipsychotics

N05AF - Thioxanthene derivatives

N05AF01 - Flupentixol

5.4 Absorption, Distribution and Excretion

Absorption

Following oral administration, flupentixol is readily absorbed from the gastrointestinal tract, with oral bioavailability of about 40%. T_max ranges from three to eight hours. Steady-state plasma levels are achieved in about seven days and following once-daily oral administration of 5 mg flupentixol, the mean minimum steady-state level was about 1.7 ng/mL (3.9 nmol/L). From the site of intramuscular injection, esterified flupentixol diffuses slowly from the oil solution and is slowly released into the extracellular fluid and the circulation to be distributed to different tissues. Peak drug concentrations are reached between four and seven days following intramuscular injection. Intramuscularly administered flupentixol is detectable in the blood three weeks after injection and reaches steady-state concentrations after about three months of repeated administration.

Route of Elimination

Fecal excretion is more predominant than renal excretion. In the feces, flupentixol is recovered in the feces mainly as the unchanged form, as well as its lipophilic metabolites, such as dealkyl-flupentixol. Flupentixol is recovered in the urine as the unchanged form as well as its hydrophilic sulfoxide and glucuronide metabolites.

Volume of Distribution

The apparent volume of distribution is about 14.1 L/kg. Following administration, the highest levels of flupentixol are found in the lungs, liver, and spleen. Lower concentrations of the drug are found in the blood and brain.

Clearance

Following oral administration, the mean systemic clearance is about 0.29 L/min.

5.5 Metabolism/Metabolites

Flupentixol is metabolized in the liver via sulfoxidation, dealkylation, and glucuronidation to form pharmacologically inactive metabolites. Flupentixol decanoate, the active ingredient in the intramuscular formulation, is hydrolyzed to flupentixol.

5.6 Biological Half-Life

The elimination half-life is about 35 hours following oral administration and three weeks following intramuscular administration.

5.7 Mechanism of Action

The mechanism of action of flupentixol is not completely understood. The antipsychotic actions are mainly thought to arise from cis(Z)-flupentixol, the active stereoisomer, acting as an antagonist at both dopamine D₁ and D₂ receptors with equal affinities. Schizophrenia is a mental illness characterized by positive (such as hallucinations and delusions) and negative (such as affect flattening and apathy) symptoms. While several neurotransmitter systems are implicated in the pathophysiologic processes leading to the development of symptoms, the dopamine and glutamate systems have been extensively studied. It is generally understood that positive symptoms of schizophrenia arise from a dysregulated striatal dopamine pathway, leading to hyperstimulation of D₂ receptors. Many antipsychotic agents work by blocking D₂ receptors as antagonists; similarly, cis(Z)-flupentixol, the active stereoisomer, is an antagonist at D₂ receptors. However, there is now evidence that antipsychotic agents can work by blocking other dopamine receptor subtypes, such as D₁, D₃, or D₄ receptors. One study showed that cis(Z)-flupentixol is an antagonist at both dopamine D₁ and D₂ receptors with equal affinities, and binds to D3 and D4 receptors with lower affinities. It also binds to alpha-1 adrenoceptors. Antidepressant effects of flupentixol are understood to be mediated by antagonism at 5-HT_2A receptors, which are commonly downregulated following repeated antidepressant treatment. Flupentixol also binds to 5-HT_2C receptors.