Ifenprodil

Identification

Generic Name
Ifenprodil
DrugBank Accession Number
DB08954
Background

N-methyl-D-aspartate (NMDA) receptors (NMDARs) are members of the ionotropic glutamate receptor family, with key roles in brain development and neurological function.1,2 NMDARs are heterotetramers that typically involve a dimer of dimers of both GluN1 and GluN2A-D subunits, with each subunit itself composed of an N-terminal domain (NTD), a ligand-binding domain (LBD), a transmembrane domain, and a C-terminal cytoplasmic domain. Binding at the LBD of the agonists glycine (or D-serine) to the GluN1 subunits and of glutamate to the GluN2 subunits is a regulatory mechanism for channel activation. In addition, allosteric modulators are known to bind at the NTDs and form another layer of regulation.1,2 One such allosteric regulator is ifenprodil, which was first shown to bind the NMDARs in the 1990s, and specifically to those NMDARs containing the GluN2B subunit.3 Further studies elucidated that ifenprodil binds strongly at the inter-subunit interface of adjacent GluN1 and GluN2B NTDs, where it acts as a non-competitive antagonist.1,2

Although ifenprodil has received considerable interest in its potential neuromodulatory activities in psychiatric conditions, including dependency4 and depression,5 it has also been shown to have an immunomodulatory effect.5,6 In an unbiased screen for compounds capable of reducing cell death induced by infection with the influenza strain H5N1, ifenprodil was found to have a protective effect against H5N1-induced lung damage, in part through its ability to alleviate the H5N1-induced cytokine storm and reduce pulmonary infiltration of neutrophils, natural killer cells, and T cells.6 Ifenprodil is being investigated for its potential utility in treating COVID-19 in an ongoing phase 2b/3 clinical trial (NCT04382924).7

Type
Small Molecule
Groups
Investigational, Withdrawn
Structure
Thumb
Weight
Average: 325.4446
Monoisotopic: 325.204179113
Chemical Formula
C21H27NO2
Synonyms
  • Ifenprodil
  • Ifenprodilum
External IDs
  • RC 61-91
  • RC 61-96

Pharmacology

Indication

Not Available

Pharmacology
Reduce drug development failure rates
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Contraindications & Blackbox Warnings
Contraindications
Avoid life-threatening adverse drug events
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Pharmacodynamics

Not Available

Mechanism of action
TargetActionsOrganism
AGlutamate receptor ionotropic, NMDA 2B
antagonist
Humans
AGlutamate receptor ionotropic, NMDA 1
antagonist
Humans
UG protein-activated inward rectifier potassium channel 1
antagonist
Humans
UG protein-activated inward rectifier potassium channel 2
antagonist
Humans
UG protein-activated inward rectifier potassium channel 4
antagonist
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Not Available

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
1,2-BenzodiazepineThe risk or severity of adverse effects can be increased when Ifenprodil is combined with 1,2-Benzodiazepine.
AcebutololIfenprodil may decrease the antihypertensive activities of Acebutolol.
AceclofenacThe risk or severity of hypertension can be increased when Aceclofenac is combined with Ifenprodil.
AcemetacinThe risk or severity of hypertension can be increased when Ifenprodil is combined with Acemetacin.
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Ifenprodil.
AcetophenazineThe risk or severity of adverse effects can be increased when Acetophenazine is combined with Ifenprodil.
Acetylsalicylic acidThe risk or severity of hypertension can be increased when Acetylsalicylic acid is combined with Ifenprodil.
AclidiniumIfenprodil may increase the central nervous system depressant (CNS depressant) activities of Aclidinium.
AgomelatineThe risk or severity of adverse effects can be increased when Agomelatine is combined with Ifenprodil.
AlclofenacThe risk or severity of hypertension can be increased when Ifenprodil is combined with Alclofenac.
Interactions
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Food Interactions
Not Available

Products

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Product Ingredients
IngredientUNIICASInChI Key
Ifenprodil tartrate89CTB4XUF723210-58-4DMPRDSPPYMZQBT-CEAXSRTFSA-N
International/Other Brands
Cerocral (Sanofi) / Furezanil (Tsuruhara Seiyaku) / Iburonol (Towa Yakuhin) / Linbulane (Tatsumi Kagaku) / Technis (Sawai Seiyaku) / Vadilex (Sanofi) / Vasculodil (Kyowa Yakuhin) / Youajyl (Yoshindo)

Categories

ATC Codes
C04AX28 — Ifenprodil
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as 4-benzylpiperidines. These are organic compounds containing a benzyl group attached to the 4-position of a piperidine.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Piperidines
Sub Class
Benzylpiperidines
Direct Parent
4-benzylpiperidines
Alternative Parents
Phenylpropanes / Aralkylamines / 1-hydroxy-2-unsubstituted benzenoids / Trialkylamines / Secondary alcohols / 1,2-aminoalcohols / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives / Aromatic alcohols
Substituents
1,2-aminoalcohol / 1-hydroxy-2-unsubstituted benzenoid / 4-benzylpiperidine / Alcohol / Amine / Aralkylamine / Aromatic alcohol / Aromatic heteromonocyclic compound / Azacycle / Benzenoid
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
R8OE3P6O5S
CAS number
23210-56-2
InChI Key
UYNVMODNBIQBMV-UHFFFAOYSA-N
InChI
InChI=1S/C21H27NO2/c1-16(21(24)19-7-9-20(23)10-8-19)22-13-11-18(12-14-22)15-17-5-3-2-4-6-17/h2-10,16,18,21,23-24H,11-15H2,1H3
IUPAC Name
4-[2-(4-benzylpiperidin-1-yl)-1-hydroxypropyl]phenol
SMILES
CC(C(O)C1=CC=C(O)C=C1)N1CCC(CC2=CC=CC=C2)CC1

References

Synthesis Reference

U.S. Patent 3,509,164.

General References
  1. Tajima N, Karakas E, Grant T, Simorowski N, Diaz-Avalos R, Grigorieff N, Furukawa H: Activation of NMDA receptors and the mechanism of inhibition by ifenprodil. Nature. 2016 Jun 2;534(7605):63-8. doi: 10.1038/nature17679. Epub 2016 May 2. [Article]
  2. Zhu S, Paoletti P: Allosteric modulators of NMDA receptors: multiple sites and mechanisms. Curr Opin Pharmacol. 2015 Feb;20:14-23. doi: 10.1016/j.coph.2014.10.009. Epub 2014 Nov 12. [Article]
  3. Williams K: Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol Pharmacol. 1993 Oct;44(4):851-9. [Article]
  4. Sugaya N, Ogai Y, Aikawa Y, Yumoto Y, Takahama M, Tanaka M, Haraguchi A, Umeno M, Ikeda K: A randomized controlled study of the effect of ifenprodil on alcohol use in patients with alcohol dependence. Neuropsychopharmacol Rep. 2018 Mar;38(1):9-17. doi: 10.1002/npr2.12001. Epub 2018 Feb 18. [Article]
  5. Yao Y, Ju P, Liu H, Wu X, Niu Z, Zhu Y, Zhang C, Fang Y: Ifenprodil rapidly ameliorates depressive-like behaviors, activates mTOR signaling and modulates proinflammatory cytokines in the hippocampus of CUMS rats. Psychopharmacology (Berl). 2020 May;237(5):1421-1433. doi: 10.1007/s00213-020-05469-0. Epub 2020 Mar 4. [Article]
  6. Zhang C, Zhang Y, Qin Y, Zhang Q, Liu Q, Shang D, Lu H, Li X, Zhou C, Huang F, Jin N, Jiang C: Ifenprodil and Flavopiridol Identified by Genomewide RNA Interference Screening as Effective Drugs To Ameliorate Murine Acute Lung Injury after Influenza A H5N1 Virus Infection. mSystems. 2019 Dec 10;4(6). pii: 4/6/e00431-19. doi: 10.1128/mSystems.00431-19. [Article]
  7. Clinical Trial NCT04382924 [Link]
KEGG Drug
D08064
PubChem Compound
3689
PubChem Substance
310264919
ChemSpider
3561
BindingDB
50083351
RxNav
27403
ChEBI
93829
ChEMBL
CHEMBL305187
Drugs.com
Drugs.com Drug Page
Wikipedia
Ifenprodil

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2RecruitingTreatmentIdiopathic Pulmonary Fibrosis (IPF)1
2, 3CompletedTreatmentCoronavirus Disease 2019 (COVID‑19) / COVID1
1, 2CompletedTreatmentPost Traumatic Stress Disorder (PTSD)1

Pharmacoeconomics

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

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.105 mg/mLALOGPS
logP3.98ALOGPS
logP3.57ChemAxon
logS-3.5ALOGPS
pKa (Strongest Acidic)9.67ChemAxon
pKa (Strongest Basic)9.03ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area43.7 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity98.35 m3·mol-1ChemAxon
Polarizability37.52 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-004i-0319000000-a8642bda70c1638039bd

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Zinc ion binding
Specific Function
NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. In concert with DAPK1 at extrasynaptic site...
Gene Name
GRIN2B
Uniprot ID
Q13224
Uniprot Name
Glutamate receptor ionotropic, NMDA 2B
Molecular Weight
166365.885 Da
References
  1. Seppala T, Stromberg C, Mattila MJ: Effects of the novel 5-hydroxytryptamine reuptake inhibitor indalpine and ethanol on psychomotor performance. Arzneimittelforschung. 1988 Jan;38(1):98-102. [Article]
  2. Tajima N, Karakas E, Grant T, Simorowski N, Diaz-Avalos R, Grigorieff N, Furukawa H: Activation of NMDA receptors and the mechanism of inhibition by ifenprodil. Nature. 2016 Jun 2;534(7605):63-8. doi: 10.1038/nature17679. Epub 2016 May 2. [Article]
  3. Zhu S, Paoletti P: Allosteric modulators of NMDA receptors: multiple sites and mechanisms. Curr Opin Pharmacol. 2015 Feb;20:14-23. doi: 10.1016/j.coph.2014.10.009. Epub 2014 Nov 12. [Article]
  4. Williams K: Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol Pharmacol. 1993 Oct;44(4):851-9. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Voltage-gated cation channel activity
Specific Function
NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic p...
Gene Name
GRIN1
Uniprot ID
Q05586
Uniprot Name
Glutamate receptor ionotropic, NMDA 1
Molecular Weight
105371.945 Da
References
  1. Seppala T, Stromberg C, Mattila MJ: Effects of the novel 5-hydroxytryptamine reuptake inhibitor indalpine and ethanol on psychomotor performance. Arzneimittelforschung. 1988 Jan;38(1):98-102. [Article]
  2. Tajima N, Karakas E, Grant T, Simorowski N, Diaz-Avalos R, Grigorieff N, Furukawa H: Activation of NMDA receptors and the mechanism of inhibition by ifenprodil. Nature. 2016 Jun 2;534(7605):63-8. doi: 10.1038/nature17679. Epub 2016 May 2. [Article]
  3. Zhu S, Paoletti P: Allosteric modulators of NMDA receptors: multiple sites and mechanisms. Curr Opin Pharmacol. 2015 Feb;20:14-23. doi: 10.1016/j.coph.2014.10.009. Epub 2014 Nov 12. [Article]
  4. Williams K: Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol Pharmacol. 1993 Oct;44(4):851-9. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
G-protein activated inward rectifier potassium channel activity
Specific Function
This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their...
Gene Name
KCNJ3
Uniprot ID
P48549
Uniprot Name
G protein-activated inward rectifier potassium channel 1
Molecular Weight
56602.84 Da
References
  1. Kobayashi T, Washiyama K, Ikeda K: Inhibition of G protein-activated inwardly rectifying K+ channels by ifenprodil. Neuropsychopharmacology. 2006 Mar;31(3):516-24. doi: 10.1038/sj.npp.1300844. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Inward rectifier potassium channel activity
Specific Function
This potassium channel may be involved in the regulation of insulin secretion by glucose and/or neurotransmitters acting through G-protein-coupled receptors. Inward rectifier potassium channels are...
Gene Name
KCNJ6
Uniprot ID
P48051
Uniprot Name
G protein-activated inward rectifier potassium channel 2
Molecular Weight
48450.96 Da
References
  1. Kobayashi T, Washiyama K, Ikeda K: Inhibition of G protein-activated inwardly rectifying K+ channels by ifenprodil. Neuropsychopharmacology. 2006 Mar;31(3):516-24. doi: 10.1038/sj.npp.1300844. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
G-protein activated inward rectifier potassium channel activity
Specific Function
This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their...
Gene Name
KCNJ5
Uniprot ID
P48544
Uniprot Name
G protein-activated inward rectifier potassium channel 4
Molecular Weight
47667.3 Da
References
  1. Kobayashi T, Washiyama K, Ikeda K: Inhibition of G protein-activated inwardly rectifying K+ channels by ifenprodil. Neuropsychopharmacology. 2006 Mar;31(3):516-24. doi: 10.1038/sj.npp.1300844. [Article]

Drug created on May 28, 2014 17:48 / Updated on May 06, 2021 01:45