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Identification
Name Pimozide
Accession Number DB01100 (APRD00218)
Type small molecule
Groups approved
Description

A diphenylbutylpiperidine that is effective as an antipsychotic agent and as an alternative to haloperidol for the suppression of vocal and motor tics in patients with Tourette syndrome. Although the precise mechanism of action is unknown, blockade of postsynaptic dopamine receptors has been postulated. (From AMA Drug Evaluations Annual, 1994, p403)
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Pimozida [INN-Spanish]
Pimozidum [INN-Latin]
Salts Not Available
Brand names
Name Company
Neoperidole
Opiran
Orap
Brand mixtures Not Available
Categories
  • Dopamine Antagonists
  • Antipsychotic Agents
  • Anti-Dyskinesia Agents
CAS number 2062-78-4
Weight Average: 461.5462
Monoisotopic: 461.227868975
Chemical Formula C28H29F2N3O
InChI Key InChIKey=YVUQSNJEYSNKRX-UHFFFAOYSA-N
InChI
InChI=1S/C28H29F2N3O/c29-22-11-7-20(8-12-22)25(21-9-13-23(30)14-10-21)4-3-17-32-18-15-24(16-19-32)33-27-6-2-1-5-26(27)31-28(33)34/h1-2,5-14,24-25H,3-4,15-19H2,(H,31,34)
Plain Text
IUPAC Name
1-{1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl}-2,3-dihydro-1H-1,3-benzodiazol-2-one
SMILES
FC1=CC=C(C=C1)C(CCCN1CCC(CC1)N1C(=O)NC2=CC=CC=C12)C1=CC=C(F)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes
  • Diphenylmethanes
Substructures
  • Benzimidazoles
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Diphenylmethanes
  • Halobenzenes
  • Imidazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Cyanamides
  • Aryl Halides
  • Piperidines
Pharmacology
Indication Used for the suppression of motor and phonic tics in patients with Tourette's Disorder who have failed to respond satisfactorily to standard treatment.
Pharmacodynamics Pimozide is an orally active antipsychotic drug product which shares with other antipsychotics the ability to blockade dopaminergic receptors on neurons in the central nervous system. However, receptor blockade is often accompanied by a series of secondary alterations in central dopamine metabolism and function which may contribute to both pimozide's therapeutic and untoward effects. In addition, pimozide, in common with other antipsychotic drugs, has various effects on other central nervous system receptor systems which are not fully characterized. Pimozide also has less potential for inducing sedation and hypotension as it has more specific dopamine receptor blocking activity than other neuroleptic agents (and is therefore a suitable alternative to haloperidol).
Mechanism of action The ability of pimozide to suppress motor and phonic tics in Tourette's Disorder is thought to be primarily a function of its dopaminergic blocking activity. Pimozide binds and inhibits the dopamine D2 receptor in the CNS.
Absorption Greater than 50% absorption after oral administration. Serum peak appears 6-8 hours post ingestion.
Volume of distribution Not Available
Protein binding Not Available
Metabolism Notable first-pass metabolism in the liver, primarily by N-dealkylation via the cytochrome P450 isoenzymes CYP3A and CYP1A2 (and possibly CYP2D6). The activity of the two major metabolites has not been determined.
Route of elimination Not Available
Half life 29 ± 10 hours (single-dose study of healthy volunteers).
Clearance Not Available
Toxicity LD50 = 1100 mg/kg (rat, oral), 228 mg/kg (mouse, oral)
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Teva pharmaceuticals usa inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Orap 1 mg tablet 1.22 USD tablet
Orap 2 mg tablet 1.17 USD tablet
Orap 4 mg Tablet 0.47 USD tablet
Apo-Pimozide 4 mg Tablet 0.43 USD tablet
Apo-Pimozide 2 mg Tablet 0.24 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 214-218 °C PhysProp
water solubility 10 mg/L (at 25 °C) MERCK INDEX (1996)
logP 6.30 HANSCH,C ET AL. (1995)
pKa 8.63 EL TAYAR,N ET AL. (1985)
Predicted Properties
Property Value Source
water solubility 1.73e-03 g/l ALOGPS
logP 6.36 ALOGPS
logP 5.83 ChemAxon
logS -5.4 ALOGPS
pKa (strongest acidic) 12.9 ChemAxon
pKa (strongest basic) 8.38 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 2 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 35.58 ChemAxon
rotatable bond count 7 ChemAxon
refractivity 132.21 ChemAxon
polarizability 50.04 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00560 Link_out
KEGG Compound C07566 Link_out
PubChem Compound 16362 Link_out
PubChem Substance 46507096 Link_out
ChemSpider 15520 Link_out
ChEBI 8212 Link_out
ChEMBL 8212 Link_out
Therapeutic Targets Database DAP000316 Link_out
PharmGKB PA450965 Link_out
IUPHAR 90 Link_out
Guide to Pharmacology 90 Link_out
Drug Product Database 573817 Link_out
RxList http://www.rxlist.com/cgi/generic3/orap.htm Link_out
Drugs.com http://www.drugs.com/cdi/pimozide.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Pimozide Link_out
ATC Codes
  • N05AG02
AHFS Codes
  • 28:16.08.92
PDB Entries Not Available
FDA label Not Available
MSDS show (29 KB)
Interactions
Drug Interactions
Drug Interaction
Amprenavir Amprenavir may increase the effect and toxicity of pimozide.
Aprepitant Increased risk of cardiotoxicity and arrhythmias
Artemether Additive QTc-prolongation may occur. Concomitant therapy is contraindicated.
Atazanavir The protease inhibitor, atazanavir, may increase the effect and toxicity of pimozide.
Citalopram The SSRI, citalopram, may increase the effect and toxicity of pimozide.
Clarithromycin Increased risk of cardiotoxicity and arrhythmias
Donepezil Possible antagonism of action
Erythromycin Increased risk of cardiotoxicity and arrhythmias
Escitalopram The SSRI, escitalopram, increases the effect and toxicity of pimozide.
Fluconazole Increased risk of cardiotoxicity and arrhythmias
Fosamprenavir Amprenavir increases the effect and toxicity of pimozide
Galantamine Possible antagonism of action
Imatinib Imatinib may increase the effect and toxicity of pimozide.
Indinavir The protease inhibitor, indinavir, may increase the effect and toxicity of pimozide.
Itraconazole Increased risk of cardiotoxicity and arrhythmias
Josamycin Increased risk of cardiotoxicity and arrhythmias
Ketoconazole Increased risk of cardiotoxicity and arrhythmias
Lumefantrine Additive QTc-prolongation may occur. Concomitant therapy is contraindicated.
Mesoridazine Increased risk of cardiotoxicity and arrhythmias
Nefazodone Nefazodone may increase the effect and toxicity of pimozide.
Nelfinavir Nelfinavir increases the effect and toxicity of pimozide
Paroxetine Increased risk of cardiotoxicity and arrhythmias.
Posaconazole Contraindicated co-administration
Ritonavir The protease inhibitor, ritonavir, may increase the effect and toxicity of pimozide.
Rivastigmine Possible antagonism of action
Saquinavir The protease inhibitor, saquinavir, may increase the effect and toxicity of pimozide.
Sertraline The SSRI, sertraline, increases the effect and toxicity of pimozide.
Tacrine The therapeutic effects of the central acetylcholinesterase inhibitor (AChEI), Tacrine, and/or the anticholinergic/antipsychotic, Pimozide, may be reduced due to antagonism. This interaction may be beneficial when the anticholinergic action is a side effect. AChEIs may also augment the central neurotoxic effect of antipsychotics. Monitor for extrapyramidal symptoms and decreased efficacy of both agents.
Tacrolimus Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Telavancin Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Telithromycin Telithromycin may reduce clearance of Pimozide. Concomitant therapy is contraindicated.
Tetrabenazine May cause dopamine deficiency. Monitor for Tetrabenazine adverse effects.
Thioridazine Increased risk of cardiotoxicity and arrhythmias
Thiothixene May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
Tipranavir Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Pimozide. Concomitant therapy is contraindicated.
Toremifene Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
Trimethobenzamide Trimethobenzamide and Pimozide, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.
Trimipramine Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Triprolidine Triprolidine and Pimozide, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.
Troleandomycin Increased risk of cardiotoxicity and arrhythmias
Trospium Trospium and Pimozide, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of pimozide by decreasing its metabolism. Increased risk of QTc prolongation and development arrhythmias. Concomitant use is contraindicated.
Vorinostat Additive QTc prolongation may occur. Concomitant therapy is contraindicated.
Zileuton Increased risk of cardiotoxicity and arrhythmias
Ziprasidone Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy should be avoided.
Zuclopenthixol Additive QTc-prolonging effects increases risk of cardiac arrhythmias. Concomitant therapy is contraindicated.
Food Interactions
  • Grapefruit and grapefruit juice should be avoided throughout treatment. Grapefruit can increase serum levels of this product.
  • Take without regard to meals.
Targets

1. D(2) dopamine receptor

Pharmacological action: yes
Actions: antagonist

This is one of the five types (D1 to D5) of receptors for dopamine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase

Organism class: human
UniProt ID: P14416 Link_out
Gene: DRD2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Seeman P: Atypical antipsychotics: mechanism of action. Can J Psychiatry. 2002 Feb;47(1):27-38. Pubmed
  3. Silva MR, Bernardi MM, Cruz-Casallas PE, Felicio LF: Pimozide injections into the Nucleus accumbens disrupt maternal behaviour in lactating rats. Pharmacol Toxicol. 2003 Jul;93(1):42-7. Pubmed
  4. Muscat R, Sampson D, Willner P: Dopaminergic mechanism of imipramine action in an animal model of depression. Biol Psychiatry. 1990 Aug 1;28(3):223-30. Pubmed
  5. Zarrindast MR, Heidari MR: On the mechanisms by which theophylline changes core body temperature in mice. Eur J Pharmacol. 1994 May 12;257(1-2):13-20. Pubmed
  6. Freedman SB, Patel S, Marwood R, Emms F, Seabrook GR, Knowles MR, McAllister G: Expression and pharmacological characterization of the human D3 dopamine receptor. J Pharmacol Exp Ther. 1994 Jan;268(1):417-26. Pubmed
  7. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. Pubmed
  8. Murphy LL, Adrian BA, Kohli M: Inhibition of luteinizing hormone secretion by delta9-tetrahydrocannabinol in the ovariectomized rat: effect of pretreatment with neurotransmitter or neuropeptide receptor antagonists. Steroids. 1999 Sep;64(9):664-71. Pubmed

2. D(3) dopamine receptor

Pharmacological action: yes
Actions: antagonist

This is one of the five types (D1 to D5) of receptors for dopamine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase

Organism class: human
UniProt ID: P35462 Link_out
Gene: DRD3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Freedman SB, Patel S, Marwood R, Emms F, Seabrook GR, Knowles MR, McAllister G: Expression and pharmacological characterization of the human D3 dopamine receptor. J Pharmacol Exp Ther. 1994 Jan;268(1):417-26. Pubmed

3. Potassium voltage-gated channel subfamily H member 2

Pharmacological action: yes
Actions: inhibitor

Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoform 3 has no channel activity by itself, but modulates channel characteristics when associated with isoform 1

Organism class: human
UniProt ID: Q12809 Link_out
Gene: KCNH2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kang J, Wang L, Cai F, Rampe D: High affinity blockade of the HERG cardiac K(+) channel by the neuroleptic pimozide. Eur J Pharmacol. 2000 Mar 31;392(3):137-40. Pubmed
  2. Osypenko VM, Degtiar VIe, Naid’onov VG, Shuba IaM: [Blockade of HERG K+ channels expressed in Xenopus oocytes by antipsychotic agents] Fiziol Zh. 2001;47(1):17-25. Pubmed
  3. Shuba YM, Degtiar VE, Osipenko VN, Naidenov VG, Woosley RL: Testosterone-mediated modulation of HERG blockade by proarrhythmic agents. Biochem Pharmacol. 2001 Jul 1;62(1):41-9. Pubmed
  4. Kang J, Chen XL, Rampe D: The antipsychotic drugs sertindole and pimozide block erg3, a human brain K(+) channel. Biochem Biophys Res Commun. 2001 Aug 24;286(3):499-504. Pubmed

4. Calmodulin

Pharmacological action: unknown
Actions: inhibitor

Calmodulin mediates the control of a large number of enzymes and other proteins by Ca(2+). Among the enzymes to be stimulated by the calmodulin-Ca(2+) complex are a number of protein kinases and phosphatases

Organism class: human
UniProt ID: P62158 Link_out
Gene: CALM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Papadopoulos V, Brown AS, Hall PF: Calcium-calmodulin-dependent phosphorylation of cytoskeletal proteins from adrenal cells. Mol Cell Endocrinol. 1990 Dec 3;74(2):109-23. Pubmed
  2. Wang XB, Sato N, Greer MA, Greer SE, McAdams S: Role of extracellular calcium and calmodulin in prolactin secretion induced by hyposmolarity, thyrotropin-releasing hormone, and high K+ in GH4C1 cells. Acta Endocrinol (Copenh). 1990 Aug;123(2):218-24. Pubmed
  3. Strobl JS, Kirkwood KL, Lantz TK, Lewine MA, Peterson VA, Worley JF 3rd: Inhibition of human breast cancer cell proliferation in tissue culture by the neuroleptic agents pimozide and thioridazine. Cancer Res. 1990 Sep 1;50(17):5399-405. Pubmed
  4. Cimino M, Weiss B: Characteristics of the binding of phenoxybenzamine to calmodulin. Biochem Pharmacol. 1988 Jul 15;37(14):2739-45. Pubmed
  5. Mody I, Baimbridge KG, Miller JJ: Blockade of tetanic- and calcium-induced long-term potentiation in the hippocampal slice preparation by neuroleptics. Neuropharmacology. 1984 Jun;23(6):625-31. Pubmed
Enzymes

1. Cytochrome P450 3A5

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

2. Cytochrome P450 3A7

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P24462 Link_out
Gene: CYP3A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

3. Cytochrome P450 3A4

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 1A2

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 2C19

Actions: inhibitor

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

6. Cytochrome P450 2D6

Actions: inhibitor

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

7. Cytochrome P450 2E1

Actions: inhibitor

Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms

UniProt ID: P05181 Link_out
Gene: CYP2E1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J: Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem. 2003 Apr 24;46(9):1716-25. Pubmed
  2. Ibrahim S, Peggins J, Knapton A, Licht T, Aszalos A: Influence of antipsychotic, antiemetic, and Ca(2+) channel blocker drugs on the cellular accumulation of the anticancer drug daunorubicin: P-glycoprotein modulation. J Pharmacol Exp Ther. 2000 Dec;295(3):1276-83. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19