Identification

Name
Remoxipride
Accession Number
DB00409  (APRD00316)
Type
Small Molecule
Groups
Approved, Withdrawn
Description

An antipsychotic agent that is specific for dopamine D2 receptors. It has been shown to be effective in the treatment of schizophrenia.

Structure
Thumb
Synonyms
  • Remoxiprida
  • Remoxipride
  • Remoxipridum
External IDs
A 33547 / A-33547 / FLA 731 / FLA-731(-)
Product Ingredients
IngredientUNIICASInChI Key
Remoxipride hydrochlorideMH4OU8RWCW117591-79-4SPFVHFBNXPARTR-IDMXKUIJSA-N
International/Other Brands
Roxiam
Categories
UNII
0223RD59PE
CAS number
80125-14-0
Weight
Average: 371.269
Monoisotopic: 370.089205259
Chemical Formula
C16H23BrN2O3
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[C@H]1CNC(=O)C1=C(OC)C=CC(Br)=C1OC

Pharmacology

Indication

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

Pharmacodynamics

Remoxipride, a substituted benzamide, is a selective D2 receptor antagonist. It has been shown to be effective in the treatment of schizophrenia. Some antipsychotics block domapinergic receptors as well as cholinergic, noradrenergic and histaminergic receptors. Remoxipride was developed to act specifically on the dopamine D2 receptor. As a consequence, several undesired side effects can occur. Patients often feel they are not taking any antipsychotic drug. It has a potent affinity for the sigma receptor, but it is unclear whether it is a sigma agonist or antagonist. The contribution of this property to its clinical profile is unknown. Blocking the D2 dopamine receptor is known to cause relapse in patients that have achieved remission from depression, and such blocking also counteracts the effectiveness of SSRI medication.

Mechanism of action

Remoxipride acts as an antagonist at the D2 dopamine receptor. It is believed that overactivity of dopamine systems in the mesolimbic pathway may contribute to the "positive symptoms" of schizophrenia (such as delusions and hallucinations), whereas problems with dopamine function in the mesocortical pathway may be responsible for the "negative symptoms", such as avolition, flat emotional response and alogia. Therefore, by decreasing the levels of dopamine in these pathways, it is thought that remoxipride is able to reduce the symptoms of schizophrenia, particularily the "positive symptoms".

TargetActionsOrganism
AD(2) dopamine receptor
antagonist
Human
UD(4) dopamine receptor
antagonist
Human
UD(3) dopamine receptor
antagonist
Human
U5-hydroxytryptamine receptor 2A
other/unknown
Human
USigma non-opioid intracellular receptor 1
antagonist
Human
Absorption

Rapidly absorbed. Absolute bioavailability is 90%.

Volume of distribution
Not Available
Protein binding

89-98%

Metabolism

No active metabolites

Route of elimination
Not Available
Half life

4-7 hours

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

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylamphetamineRemoxipride may decrease the stimulatory activities of 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamineRemoxipride may decrease the stimulatory activities of 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineRemoxipride may decrease the stimulatory activities of 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetamineRemoxipride may decrease the stimulatory activities of 4-Bromo-2,5-dimethoxyamphetamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when Remoxipride is combined with 7-Nitroindazole.
AbirateroneThe serum concentration of Remoxipride can be increased when it is combined with Abiraterone.
AcepromazineThe risk or severity of adverse effects can be increased when Remoxipride is combined with Acepromazine.
AceprometazineThe risk or severity of adverse effects can be increased when Remoxipride is combined with Aceprometazine.
AcetazolamideThe risk or severity of adverse effects can be increased when Remoxipride is combined with Acetazolamide.
AdipiplonThe risk or severity of adverse effects can be increased when Remoxipride is combined with Adipiplon.
Food Interactions
  • Take without regard to meals.

References

Synthesis Reference
US4232037
General References
Not Available
External Links
Human Metabolome Database
HMDB0014553
PubChem Compound
54477
PubChem Substance
46508689
ChemSpider
49195
BindingDB
50026045
ChEBI
92948
ChEMBL
CHEMBL22242
Therapeutic Targets Database
DAP000312
PharmGKB
PA164749051
Wikipedia
Remoxipride
ATC Codes
N05AL04 — Remoxipride

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility74 mg/LNot Available
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

Taxonomy

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
M-dimethoxybenzene / Dimethoxybenzene / Halobenzoic acid or derivatives / 3-halobenzoic acid or derivatives / Benzamide / Benzoic acid or derivatives / Phenoxy compound / Anisole / Benzoyl / Phenol ether
show 27 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Details
1. D(2) dopamine receptor
Kind
Protein
Organism
Human
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]
Details
2. D(4) dopamine receptor
Kind
Protein
Organism
Human
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. D(3) dopamine receptor
Kind
Protein
Organism
Human
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]
Kind
Protein
Organism
Human
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
Human
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
Human
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. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. 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]

Drug created on June 13, 2005 07:24 / Updated on October 10, 2018 21:43