Identification

Name
Remoxipride
Accession Number
DB00409
Description

Remoxipride is an atypical antipsychotic agent that is specific for dopamine D2 receptors.1 It gained approval in the UK in 1989 but was withdrawn in 1993 after it was found to be associated with an increased incidence of aplastic anemia.1,5

Type
Small Molecule
Groups
Approved, Withdrawn
Structure
Thumb
Weight
Average: 371.269
Monoisotopic: 370.089205259
Chemical Formula
C16H23BrN2O3
Synonyms
  • Remoxiprida
  • Remoxipride
  • Remoxipridum
External IDs
  • A 33547
  • A-33547
  • FLA 731
  • FLA-731(-)

Pharmacology

Indication

Remoxipride is an atypical antipsychotic once used for the treatment of schizophrenia.6

Contraindications & Blackbox Warnings
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Pharmacodynamics

Remoxipride is a weak selective dopamine D2 receptor antagonist that was once used in the treatment of schizophrenia.1 It has a moderate therapeutic index and duration of action.8 Remoxipride was withdrawn due to deaths associated with aplastic anemia.5

Mechanism of action

Remoxipride is an atypical antipsychotic dopamine D2 antagonist.1 Chronic use upregulates the expression of D2 receptors, while downregulating the expression of D1 and D5 receptors in the prefrontal cortex.1 This activity may be related to the antipsychotic activity of remoxipride.1 Remoxipride displays weaker binding to D2 dopaminergic receptors that dopamine.7 This weaker binding is thought to account for the reduced incidence of Parkinsonism.7 Remoxipride also increases expression of the protein Fos in the nucleus accumbens but not the dorsolateral striatum, which may be responsible for a reduced incidence of extrapyramidal symptoms.1

TargetActionsOrganism
ADopamine D2 receptor
antagonist
Humans
UDopamine D4 receptor
antagonist
Humans
UDopamine D3 receptor
antagonist
Humans
U5-hydroxytryptamine receptor 2A
other/unknown
Humans
USigma non-opioid intracellular receptor 1
antagonist
Humans
Absorption

Remoxipride is approximately 90% bioavailable.2 In patients with normal creatinine clearance, remoxipride reaches a Cmax of 5.5 ± 1.1 µmol/L, with a Tmax of 0.8 ± 0.2 h, and an AUC of 39 ± 9 µmol*h/L.2 In patients with moderate renal impairment, remoxipride reaches a Cmax of 7.7 ± 2.7 µmol/L, with a Tmax of 0.9 ± 0.4 h, and an AUC of 63 ± 34 µmol*h/L.2 In patients with severe renal impairment, remoxipride reaches a Cmax of 9.3 ± 2.3 µmol/L, with a Tmax of 1.4 ± 0.9 h, and an AUC of 123 ± 60 µmol*h/L.2

Volume of distribution

The volume of distribution of remoxipride in patients with normal creatinine clearance is 44.3 ± 8.3 L, in patients with moderate renal impairment is 37.4 ± 16.2 L, and in patients with severe renal impairment is 30.2 ± 9.4 L.2

Protein binding

Remoxipride is approximately 80% protein bound, mainly to α-1-acid glycoprotein.4

Metabolism

Remoxipride can be N-dealkylated to FLA 853, oxidized to FLA 850, or N-deethylated to FLA 838.3,2 FLA 838 can be oxidized to NCL 118 which is further hydroxylated to NCM 009.3,2 FLA 850 can be N-deethylated to NCL 118 or hydroxylated to NCM 001.3,2 NCM 001 is further N-deethylated to NCM 009.3,2 None of these metabolites have measurable activity on dopamine D2 receptors.2

Hover over products below to view reaction partners

Route of elimination

A dose of remoxipride is 89% recovered in the urine and 7% in the feces.4 10-40% of a dose of remoxipride is recovered in the urine as the unchanged parent drug.4

Half-life

The half life of remoxipride in patients with normal creatinine clearance is 5.1 ± 1.6 h, in patients with moderate renal impairment is 6.1 ± 2.6 h, and in patients with severe renal impairment is 9.9 ± 3.8 h.2

Clearance

The renal clearance of remoxipride in patients with normal creatinine clearance is 23.6 ± 7.0 mL/min, in patients with moderate renal impairment is 9.3 ± 3.8 mL/min, and in patients with severe renal impairment is 3.7 ± 2.9 mL/min.2 The systemic plasma clearance of remoxipride is 120 mL/min.4

Adverse Effects
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Toxicity

Remoxipride was withdrawn from the market after 8 cases of aplastic anemia were reported.5 Of those 8 cases, 2 were fatal.5

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe metabolism of Remoxipride can be increased when combined with Abatacept.
AbirateroneThe metabolism of Remoxipride can be decreased when combined with Abiraterone.
AcebutololThe metabolism of Remoxipride can be decreased when combined with Acebutolol.
AcetaminophenThe metabolism of Remoxipride can be decreased when combined with Acetaminophen.
AcetazolamideThe risk or severity of adverse effects can be increased when Remoxipride is combined with Acetazolamide.
AcetophenazineThe risk or severity of adverse effects can be increased when Remoxipride is combined with Acetophenazine.
AclidiniumRemoxipride may increase the central nervous system depressant (CNS depressant) activities of Aclidinium.
AdalimumabThe metabolism of Remoxipride can be increased when combined with Adalimumab.
AgomelatineThe risk or severity of adverse effects can be increased when Remoxipride is combined with Agomelatine.
AlfentanilThe risk or severity of adverse effects can be increased when Remoxipride is combined with Alfentanil.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
Not Available

Products

Product Ingredients
IngredientUNIICASInChI Key
Remoxipride hydrochlorideMH4OU8RWCW117591-79-4SPFVHFBNXPARTR-IDMXKUIJSA-N
International/Other Brands
Roxiam

Categories

ATC Codes
N05AL04 — Remoxipride
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as dimethoxybenzenes. These are organic aromatic compounds containing a monocyclic benzene moiety carrying exactly two methoxy groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Methoxybenzenes
Direct Parent
Dimethoxybenzenes
Alternative Parents
3-halobenzoic acids and derivatives / Benzamides / Phenoxy compounds / Anisoles / Benzoyl derivatives / Alkyl aryl ethers / Bromobenzenes / Aryl bromides / N-alkylpyrrolidines / Trialkylamines
show 7 more
Substituents
3-halobenzoic acid or derivatives / Alkyl aryl ether / Amine / Amino acid or derivatives / Anisole / Aromatic heteromonocyclic compound / Aryl bromide / Aryl halide / Azacycle / Benzamide
show 27 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
0223RD59PE
CAS number
80125-14-0
InChI Key
GUJRSXAPGDDABA-NSHDSACASA-N
InChI
InChI=1S/C16H23BrN2O3/c1-4-19-9-5-6-11(19)10-18-16(20)14-13(21-2)8-7-12(17)15(14)22-3/h7-8,11H,4-6,9-10H2,1-3H3,(H,18,20)/t11-/m0/s1
IUPAC Name
3-bromo-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-2,6-dimethoxybenzamide
SMILES
CCN1CCC[[email protected]]1CNC(=O)C1=C(OC)C=CC(Br)=C1OC

References

Synthesis Reference
US4232037
General References
  1. Nadal R: Pharmacology of the atypical antipsychotic remoxipride, a dopamine D2 receptor antagonist. CNS Drug Rev. 2001 Fall;7(3):265-82. doi: 10.1111/j.1527-3458.2001.tb00199.x. [PubMed:11607043]
  2. Movin-Osswald G, Boelaert J, Hammarlund-Udenaes M, Nilsson LB: The pharmacokinetics of remoxipride and metabolites in patients with various degrees of renal function. Br J Clin Pharmacol. 1993 Jun;35(6):615-22. doi: 10.1111/j.1365-2125.1993.tb04191.x. [PubMed:8329289]
  3. Mohell N, Sallemark M, Rosqvist S, Malmberg A, Hogberg T, Jackson DM: Binding characteristics of remoxipride and its metabolites to dopamine D2 and D3 receptors. Eur J Pharmacol. 1993 Jul 6;238(1):121-5. doi: 10.1016/0014-2999(93)90515-j. [PubMed:8405075]
  4. von Bahr C, Movin G, Yisak WA, Jostell KG, Widman M: Clinical pharmacokinetics of remoxipride. Acta Psychiatr Scand Suppl. 1990;358:41-4. doi: 10.1111/j.1600-0447.1990.tb05284.x. [PubMed:1978486]
  5. King DJ, Wager E: Haematological safety of antipsychotic drugs. J Psychopharmacol. 1998;12(3):283-8. doi: 10.1177/026988119801200309. [PubMed:10958256]
  6. Subramanian S, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Kissling W, Leucht S, Komossa K: Zotepine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2010 Oct 6;(10):CD006628. doi: 10.1002/14651858.CD006628.pub3. [PubMed:20927748]
  7. Seeman P, Tallerico T: Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry. 1998 Mar;3(2):123-34. [PubMed:9577836]
  8. Farde L, Grind M, Nilsson MI, Ogenstad S, Sedvall G: Remoxipride--a new potential antipsychotic drug. Pharmacological effects and pharmacokinetics following repeated oral administration in male volunteers. Psychopharmacology (Berl). 1988;95(2):157-61. doi: 10.1007/BF00174501. [PubMed:2901121]
Human Metabolome Database
HMDB0014553
PubChem Compound
54477
PubChem Substance
46508689
ChemSpider
49195
BindingDB
50026045
RxNav
35350
ChEBI
92948
ChEMBL
CHEMBL22242
ZINC
ZINC000002021799
Therapeutic Targets Database
DAP000312
PharmGKB
PA164749051
Wikipedia
Remoxipride

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP2.10HOEGBERG,T ET AL. 1986
Predicted Properties
PropertyValueSource
Water Solubility0.127 mg/mLALOGPS
logP2.94ALOGPS
logP2.34ChemAxon
logS-3.5ALOGPS
pKa (Strongest Acidic)13.06ChemAxon
pKa (Strongest Basic)8.4ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area50.8 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity90.56 m3·mol-1ChemAxon
Polarizability36.25 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9705
Caco-2 permeable+0.5835
P-glycoprotein substrateSubstrate0.775
P-glycoprotein inhibitor INon-inhibitor0.674
P-glycoprotein inhibitor IINon-inhibitor0.6462
Renal organic cation transporterNon-inhibitor0.5402
CYP450 2C9 substrateNon-substrate0.868
CYP450 2D6 substrateSubstrate0.8919
CYP450 3A4 substrateSubstrate0.5728
CYP450 1A2 substrateNon-inhibitor0.6776
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5505
Ames testNon AMES toxic0.6906
CarcinogenicityNon-carcinogens0.8373
BiodegradationNot ready biodegradable0.9703
Rat acute toxicity2.8267 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.802
hERG inhibition (predictor II)Inhibitor0.7976
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Details
1. Dopamine D2 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Potassium channel regulator activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name
DRD2
Uniprot ID
P14416
Uniprot Name
D(2) dopamine receptor
Molecular Weight
50618.91 Da
References
  1. Seeman P: Atypical antipsychotics: mechanism of action. Can J Psychiatry. 2002 Feb;47(1):27-38. [PubMed:11873706]
  2. Lang AE, Sandor P, Duff J: Remoxipride in Parkinson's disease: differential response in patients with dyskinesias fluctuations versus psychosis. Clin Neuropharmacol. 1995 Feb;18(1):39-45. [PubMed:8665533]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  4. Mohell N, Sallemark M, Rosqvist S, Malmberg A, Hogberg T, Jackson DM: Binding characteristics of remoxipride and its metabolites to dopamine D2 and D3 receptors. Eur J Pharmacol. 1993 Jul 6;238(1):121-5. doi: 10.1016/0014-2999(93)90515-j. [PubMed:8405075]
Details
2. Dopamine D4 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Sh3 domain binding
Specific Function
Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Its activity is mediated by G proteins ...
Gene Name
DRD4
Uniprot ID
P21917
Uniprot Name
D(4) dopamine receptor
Molecular Weight
48359.86 Da
References
  1. Seeman P, Corbett R, Van Tol HH: Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors. Neuropsychopharmacology. 1997 Feb;16(2):93-110; discussion 111-35. [PubMed:9015795]
Details
3. Dopamine D3 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
G-protein coupled amine receptor activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase. Promotes cell proliferation.
Gene Name
DRD3
Uniprot ID
P35462
Uniprot Name
D(3) dopamine receptor
Molecular Weight
44224.335 Da
References
  1. Christian AJ, Goodwin AK, Baker LE: Antagonism of the discriminative stimulus effects of (+)-7-OH-DPAT by remoxipride but not PNU-99194A. Pharmacol Biochem Behav. 2001 Mar;68(3):371-7. [PubMed:11325388]
  2. Mohell N, Sallemark M, Rosqvist S, Malmberg A, Hogberg T, Jackson DM: Binding characteristics of remoxipride and its metabolites to dopamine D2 and D3 receptors. Eur J Pharmacol. 1993 Jul 6;238(1):121-5. doi: 10.1016/0014-2999(93)90515-j. [PubMed:8405075]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Other/unknown
General Function
Virus receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodop...
Gene Name
HTR2A
Uniprot ID
P28223
Uniprot Name
5-hydroxytryptamine receptor 2A
Molecular Weight
52602.58 Da
References
  1. Seeman P, Corbett R, Van Tol HH: Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors. Neuropsychopharmacology. 1997 Feb;16(2):93-110; discussion 111-35. [PubMed:9015795]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Opioid receptor activity
Specific Function
Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma m...
Gene Name
SIGMAR1
Uniprot ID
Q99720
Uniprot Name
Sigma non-opioid intracellular receptor 1
Molecular Weight
25127.52 Da
References
  1. Lang A, Soosaar A, Koks S, Volke V, Bourin M, Bradwejn J, Vasar E: Pharmacological comparison of antipsychotic drugs and sigma-antagonists in rodents. Pharmacol Toxicol. 1994 Sep-Oct;75(3-4):222-7. [PubMed:7800667]
  2. Okuyama S: [Atypical antipsychotic profiles of sigma receptor ligands]. Nihon Yakurigaku Zasshi. 1999 Jul;114(1):13-23. [PubMed:10562961]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
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...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Marsh JC, Chowdry J, Parry-Jones N, Ellis SW, Muir KR, Gordon-Smith EC, Tucker GT: Study of the association between cytochromes P450 2D6 and 2E1 genotypes and the risk of drug and chemical induced idiosyncratic aplastic anaemia. Br J Haematol. 1999 Feb;104(2):266-70. [PubMed:10050706]
  2. Movin-Osswald G, Boelaert J, Hammarlund-Udenaes M, Nilsson LB: The pharmacokinetics of remoxipride and metabolites in patients with various degrees of renal function. Br J Clin Pharmacol. 1993 Jun;35(6):615-22. doi: 10.1111/j.1365-2125.1993.tb04191.x. [PubMed:8329289]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
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 un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Rane A, Liu Z, Levol R, Bjelfman C, Thyr C, Ericson H, Hansson T, Henderson C, Wolf CR: Differential effects of neuroleptic agents on hepatic cytochrome P-450 isozymes in the male rat. Biochim Biophys Acta. 1996 Aug 29;1291(1):60-6. doi: 10.1016/0304-4165(96)00046-3. [PubMed:8781526]
Kind
Protein
Organism
Rat
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
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 un...
Gene Name
Cyp2b1
Uniprot ID
P00176
Uniprot Name
Cytochrome P450 2B1
Molecular Weight
55933.06 Da
References
  1. Rane A, Liu Z, Levol R, Bjelfman C, Thyr C, Ericson H, Hansson T, Henderson C, Wolf CR: Differential effects of neuroleptic agents on hepatic cytochrome P-450 isozymes in the male rat. Biochim Biophys Acta. 1996 Aug 29;1291(1):60-6. doi: 10.1016/0304-4165(96)00046-3. [PubMed:8781526]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
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 react...

Components:
References
  1. Rane A, Liu Z, Levol R, Bjelfman C, Thyr C, Ericson H, Hansson T, Henderson C, Wolf CR: Differential effects of neuroleptic agents on hepatic cytochrome P-450 isozymes in the male rat. Biochim Biophys Acta. 1996 Aug 29;1291(1):60-6. doi: 10.1016/0304-4165(96)00046-3. [PubMed:8781526]

Carriers

Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...

Components:
References
  1. Movin-Osswald G, Boelaert J, Hammarlund-Udenaes M, Nilsson LB: The pharmacokinetics of remoxipride and metabolites in patients with various degrees of renal function. Br J Clin Pharmacol. 1993 Jun;35(6):615-22. doi: 10.1111/j.1365-2125.1993.tb04191.x. [PubMed:8329289]

Drug created on June 13, 2005 07:24 / Updated on July 16, 2020 10:16

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