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targets (8) enzymes (2)
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Identification
Name Sertindole
Accession Number DB06144
Type small molecule
Groups approved, withdrawn
Description

Sertindole, a neuroleptic, is one of the newer antipsychotic medications available. Serdolect is developed by the Danish pharmaceutical company H. Lundbeck. Like the other atypical antipsychotics, it has activity at dopamine and serotonin receptors in the brain. It is used in the treatment of schizophrenia. It is classified chemically as a phenylindole derivative. It was first marketed in 1996 in several European countries before being withdrawn two years later because of numerous cardiac adverse effects. It has once again been approved and should soon be available on the French and Australian market.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Sertindol [inn-spanish]
  • Sertindolum [inn-latin]
Brand names
  • Serdolect
  • Serlect
Brand name mixtures Not Available
Categories
  • Neuroleptics
  • Antipsychotic Agents
CAS number 106516-24-9
Weight Average: 440.941
Monoisotopic: 440.177917386
Chemical Formula C24H26ClFN4O
InChI Key InChIKey=GZKLJWGUPQBVJQ-UHFFFAOYSA-N
InChI
InChI=1S/C24H26ClFN4O/c25-18-1-6-23-21(15-18)22(16-30(23)20-4-2-19(26)3-5-20)17-7-10-28(11-8-17)13-14-29-12-9-27-24(29)31/h1-6,15-17H,7-14H2,(H,27,31)
Plain Text
IUPAC Name
1-(2-{4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]piperidin-1-yl}ethyl)imidazolidin-2-one
SMILES
FC1=CC=C(C=C1)N1C=C(C2CCN(CCN3CCNC3=O)CC2)C2=C1C=CC(Cl)=C2
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication Used in the treatment of schizophrenia.
Pharmacodynamics Sertindole is an atypical antipsychotic at least as effective as haloperidol and risperidone in the treatment of neuroleptic-responsive schizophrenia. Sertindole improves negative symptoms, and is also effective for the treatment of neuroleptic-resistant schizophrenia. Sertindole is generally well tolerated and is associated with a low rate of extrapyramidal symptoms (EPS).
Mechanism of action Sertindole is an antipsychotic drug with affinity for dopamine D2, serotonin 5-HT2A and 5-HT2C, and alpha1-adrenoreceptors. Preclinical studies suggest that sertindole acts preferentially on limbic and cortical dopaminergic neurons and clinical trials have confirmed that sertindole is effective at a low dopamine D2 occupancy level.
Absorption Orally available.
Volume of distribution Not Available
Protein binding Not Available
Metabolism

Hepatic. Sertindole is metabolized by cytochrome P450 isoenzymes CYP 2D6 and CYP 3A4.
Route of elimination Not Available
Half life 3 days
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers Not Available
Dosage forms Not Available
Prices Not Available
Patents Not Available
Properties
State solid
Melting point Not Available
Experimental Properties Not Available
Predicted Properties
Property Value Source
water solubility 9.63e-03 g/l ALOGPS
logP 4.29 ALOGPS
logP 3.57 ChemAxon Molconvert
logS -4.66 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 2 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 40.51 ChemAxon Molconvert
rotatable bond count 5 ChemAxon Molconvert
refractivity 131.77 ChemAxon Molconvert
polarizability 47.17 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Kane JM, Tamminga CA: Sertindole (Serdolect): preclinical and clinical findings of a new atypical antipsychotic. Expert Opin Investig Drugs. 1997 Nov;6(11):1729-41. Pubmed
  2. Lewis R, Bagnall AM, Leitner M: Sertindole for schizophrenia. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD001715. Pubmed
  3. Perquin LN: Treatment with the new antipsychotic sertindole for late-occurring undesirable movement effects. Int Clin Psychopharmacol. 2005 Nov;20(6):335-8. Pubmed
  4. Murdoch D, Keating GM: Sertindole : a review of its use in schizophrenia. CNS Drugs. 2006;20(3):233-55. Pubmed
  5. Sertindole: new drug. Another “atypical” neuroleptic; QT prolongation. Prescrire Int. 2007 Apr;16(88):59-62. Pubmed
  6. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. Pubmed
  7. Hertel P: Comparing sertindole to other new generation antipsychotics on preferential dopamine output in limbic versus striatal projection regions: mechanism of action. Synapse. 2006 Dec 1;60(7):543-52. Pubmed
External Links
Resource Link
KEGG Drug D00561 Link_out
KEGG Compound C07567 Link_out
PubChem Compound 60149 Link_out
PubChem Substance 46504717 Link_out
ChemSpider 54229 Link_out
ChEBI 9122 Link_out
ChEMBL 9122 Link_out
Therapeutic Targets Database DAP000832 Link_out
Drug Product Database 0 Link_out
Wikipedia http://en.wikipedia.org/wiki/Sertindole Link_out
ATC Codes
  • N05AE03
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
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. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. Pubmed
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  3. Mork A, Witten LM, Arnt J: Effect of sertindole on extracellular dopamine, acetylcholine, and glutamate in the medial prefrontal cortex of conscious rats: a comparison with risperidone and exploration of mechanisms involved. Psychopharmacology (Berl). 2009 Sep;206(1):39-49. Epub 2009 Jun 9. Pubmed
  4. Seeman P: Dopamine D2 receptors moderately elevated by sertindole. Synapse. 2008 May;62(5):389-93. Pubmed
  5. Cincotta SL, Rodefer JS: Emerging role of sertindole in the management of schizophrenia. Neuropsychiatr Dis Treat. 2010 Sep 7;6:429-41. Pubmed

2. 5-hydroxytryptamine 2A receptor

Pharmacological action: yes
Actions: antagonist

This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. This receptor is involved in tracheal smooth muscle contraction, bronchoconstriction, and control of aldosterone production

Organism class: human
UniProt ID: P28223 Link_out
Gene: HTR2A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. Pubmed
  2. Schreiber R, Brocco M, Millan MJ: Blockade of the discriminative stimulus effects of DOI by MDL 100,907 and the ‘atypical’ antipsychotics, clozapine and risperidone. Eur J Pharmacol. 1994 Oct 13;264(1):99-102. Pubmed
  3. Hietala J, Kuonnamaki M, Palvimaki EP, Laakso A, Majasuo H, Syvalahti E: Sertindole is a serotonin 5-HT2c inverse agonist and decreases agonist but not antagonist binding to 5-HT2c receptors after chronic treatment. Psychopharmacology (Berl). 2001 Sep;157(2):180-7. Pubmed

3. 5-hydroxytryptamine 2C receptor

Pharmacological action: yes
Actions: antagonist

This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system

Organism class: human
UniProt ID: P28335 Link_out
Gene: HTR2C Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. Pubmed
  2. Hietala J, Kuonnamaki M, Palvimaki EP, Laakso A, Majasuo H, Syvalahti E: Sertindole is a serotonin 5-HT2c inverse agonist and decreases agonist but not antagonist binding to 5-HT2c receptors after chronic treatment. Psychopharmacology (Berl). 2001 Sep;157(2):180-7. Pubmed

4. 5-hydroxytryptamine 6 receptor

Pharmacological action: yes
Actions: antagonist

This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase. It has a high affinity for tricyclic psychotropic drugs

Organism class: human
UniProt ID: P50406 Link_out
Gene: HTR6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Pouzet B, Didriksen M, Arnt J: Effects of the 5-HT receptor antagonist, SB-271046, in animal models for schizophrenia. Pharmacol Biochem Behav. 2002 Apr;71(4):635-43. Pubmed
  2. Mork A, Witten LM, Arnt J: Effect of sertindole on extracellular dopamine, acetylcholine, and glutamate in the medial prefrontal cortex of conscious rats: a comparison with risperidone and exploration of mechanisms involved. Psychopharmacology (Berl). 2009 Sep;206(1):39-49. Epub 2009 Jun 9. Pubmed

5. Potassium voltage-gated channel subfamily H member 2

Pharmacological action: unknown
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. Rampe D, Murawsky MK, Grau J, Lewis EW: The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. J Pharmacol Exp Ther. 1998 Aug;286(2):788-93. Pubmed
  2. 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
  3. Tang W, Kang J, Wu X, Rampe D, Wang L, Shen H, Li Z, Dunnington D, Garyantes T: Development and evaluation of high throughput functional assay methods for HERG potassium channel. J Biomol Screen. 2001 Oct;6(5):325-31. Pubmed

6. Alpha-1A adrenergic receptor

Pharmacological action: unknown

This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. Its effect is mediated by G(q) and G(11) proteins

Organism class: human
UniProt ID: P35348 Link_out
Gene: ADRA1A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. Pubmed
  2. Hietala J, Kuonnamaki M, Palvimaki EP, Laakso A, Majasuo H, Syvalahti E: Sertindole is a serotonin 5-HT2c inverse agonist and decreases agonist but not antagonist binding to 5-HT2c receptors after chronic treatment. Psychopharmacology (Berl). 2001 Sep;157(2):180-7. Pubmed

7. Alpha-1B adrenergic receptor

Pharmacological action: unknown

This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system

Organism class: human
UniProt ID: P35368 Link_out
Gene: ADRA1B Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. Pubmed

8. Alpha-1D adrenergic receptor

Pharmacological action: unknown

This alpha-adrenergic receptor mediates its effect through the influx of extracellular calcium

Organism class: human
UniProt ID: P25100 Link_out
Gene: ADRA1D Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. Pubmed
Enzymes

1. Cytochrome P450 2D6

Actions: substrate

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

2. Cytochrome P450 3A4

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 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. 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
Comments
Drug created on November 19, 2007 09:49 / Updated on April 19, 2011 15:15

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.