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Identification
NameMemantine
Accession NumberDB01043  (APRD00221)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Memantine is an amantadine derivative with low to moderate-affinity for NMDA receptors. It is a noncompetitive NMDA receptor antagonist that binds preferentially to NMDA receptor-operated cation channels. It blocks the effects of excessive levels of glutamate that may lead to neuronal dysfunction. It is under investigation for the treatment of Alzheimer’s disease, but there has been no clinical support for the prevention or slowing of disease progression.

Structure
Thumb
Synonyms
SynonymLanguageCode
1-Amino-3,5-dimethyladamantaneNot AvailableNot Available
1,3-Dimethyl-5-adamantanamineNot AvailableNot Available
3,5-Dimethyl-1-adamantanamineNot AvailableNot Available
3,5-Dimethyl-1-aminoadamantaneNot AvailableNot Available
3,5-Dimethyltricyclo(3.3.1.1(3,7))decan-1-amineNot AvailableNot Available
MemantinaSpanishINN
MemantineNot AvailableINN
MemantinumLatinINN
Salts
Name/CAS Structure Properties
Memantine Hydrochloride
41100-52-1
Thumb
  • InChI Key: LDDHMLJTFXJGPI-UHFFFAOYNA-N
  • Monoisotopic Mass: 215.144077416
  • Average Mass: 215.763
DBSALT000456
Brand names
NameCompany
AbixaNot Available
AkatinolNot Available
AxuraNot Available
EbixaNot Available
MemoxNot Available
NamendaNot Available
Brand mixturesNot Available
Categories
CAS number19982-08-2
WeightAverage: 179.3018
Monoisotopic: 179.167399677
Chemical FormulaC12H21N
InChI KeyBUGYDGFZZOZRHP-UHFFFAOYSA-N
InChI
InChI=1S/C12H21N/c1-10-3-9-4-11(2,6-10)8-12(13,5-9)7-10/h9H,3-8,13H2,1-2H3
IUPAC Name
3,5-dimethyladamantan-1-amine
SMILES
CC12CC3CC(C)(C1)CC(N)(C3)C2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganonitrogen Compounds
ClassAmines
SubclassPolyamines
Direct parentPolyamines
Alternative parentsMonoalkylamines
Substituentsprimary aliphatic amine; primary amine
Classification descriptionThis compound belongs to the polyamines. These are compounds containing more than one amine group.
Pharmacology
IndicationFor the treatment of moderate to severe dementia of the Alzheimer's type.
PharmacodynamicsMemantine, an amantadine derivative, is an NMDA receptor antagonist used in the treatment of Alzheimer's disease. It differs from traditional agents used in Alzheimer's disease by acting on glutamatergic neurotransmission, rather than cholinergic. There is some evidence that dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is involved in the aetiology of Alzheimer's disease (Cacabelos et al., 1999). As such, targeting the glutamatergic system, specifically NMDA receptors, was a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic system. A systematic review of randomised controlled trials found that memantine has a positive effect on cognition, mood, behaviour, and the ability to perform daily activities. There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease.
Mechanism of actionMemantine exerts its action through uncompetitive NMDA receptor antagonism, binding preferentially to the NMDA receptor-operated cation channels. Prolonged increased levels of glutamate in the brain of demented patients are sufficient to counter the voltage-dependent block of NMDA receptors by Mg2+ ions and allow continuous influx of Ca2+ ions into cells, ultimately resulting in neuronal degeneration. Studies suggest that memantine binds more effectively than Mg2+ ions at the NMDA receptor, and thereby effectively blocks this prolonged influx of Ca2+ ions through the NMDA channel whilst preserving the transient physiological activation of the channels by higher concentrations of synaptically released glutamate. Thus memantine protects against chronically elevated concentrations of glutamate. Memantine also has antagonistic activity at the type 3 serotonergic (5-HT3) receptor with a potency that is similar to that at the NMDA receptor, and lower antagonistic activity at the nicotinic acetylcholine receptor. This drug has no affinity for γ-aminobutyric acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, or glycine receptors or for voltage-dependent calcium, sodium, or potassium channels.
AbsorptionWell absorbed orally with a bioavailability of approximately 100%. Peak plasma concentrations are reached in 3-7 hours. Food has no effect on absorption.
Volume of distribution
  • 9 to 11 L/kg
Protein binding45%
Metabolism

Excreted largely unchanged. About 20% is metabolized to 1-amino-3-hydroxymethyl-5-methyl-adamantane and 3-amino-1-hydroxy-5,7-dimethyl-adamantane.

SubstrateEnzymesProduct
Memantine
Not Available
1-amino-3-hydroxymethyl-5-methyl-adamantaneDetails
Memantine
Not Available
3-amino-1-hydroxy-5,7-dimethyl-adamantaneDetails
Route of eliminationMemantine undergoes partial hepatic metabolism. About 48% of administered drug is excreted unchanged in urine; the remainder is converted primarily to three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine. It is excreted predominantly in the urine, unchanged.
Half life60-100 hours
ClearanceNot Available
ToxicitySide effects include pain, abnormal crying, leg pain, fever, increased apetite. Adverse drug reactions include: dizziness, confusion, headache, hallucinations, tiredness. Less common side effects include: vomiting, anxiety, hypertonia, cystitis, and increased libido. Doses of up to 400 mg have been tolerated.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9939
Blood Brain Barrier + 0.9823
Caco-2 permeable + 0.6082
P-glycoprotein substrate Non-substrate 0.6403
P-glycoprotein inhibitor I Non-inhibitor 0.82
P-glycoprotein inhibitor II Non-inhibitor 0.7555
Renal organic cation transporter Non-inhibitor 0.7774
CYP450 2C9 substrate Non-substrate 0.8213
CYP450 2D6 substrate Non-substrate 0.6153
CYP450 3A4 substrate Non-substrate 0.5319
CYP450 1A2 substrate Non-inhibitor 0.9327
CYP450 2C9 substrate Non-inhibitor 0.9281
CYP450 2D6 substrate Non-inhibitor 0.872
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6795
Ames test Non AMES toxic 0.6945
Carcinogenicity Non-carcinogens 0.7426
Biodegradation Not ready biodegradable 0.9633
Rat acute toxicity 2.3455 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9839
hERG inhibition (predictor II) Non-inhibitor 0.6818
Pharmacoeconomics
Manufacturers
  • Forest laboratories inc
  • Sun pharmaceutical industries ltd
  • Dr reddys laboratories ltd
Packagers
Dosage forms
FormRouteStrength
TabletOral10mg
Prices
Unit descriptionCostUnit
Namenda 10 mg tablet3.38USDtablet
Namenda 5 mg tablet3.32USDtablet
Namenda 5-10 mg titration pk3.32USDeach
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States50617031995-04-112015-04-11
Canada24264922006-10-032023-05-08
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point258 °CPhysProp
water solubility35 mg/mL (HCl salt), 0.9 mg/mL for free baseNot Available
logP3.28HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.0455ALOGPS
logP3.31ALOGPS
logP2.07ChemAxon
logS-3.6ALOGPS
pKa (Strongest Basic)10.7ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area26.02 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity54.49 m3·mol-1ChemAxon
Polarizability21.82 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US3391142
General Reference
  1. Cacabelos R, Takeda M, Winblad B: The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer’s disease. Int J Geriatr Psychiatry. 1999 Jan;14(1):3-47. Pubmed
  2. Rogawski MA, Wenk GL: The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev. 2003 Fall;9(3):275-308. Pubmed
  3. Robinson DM, Keating GM: Memantine: a review of its use in Alzheimer’s disease. Drugs. 2006;66(11):1515-34. Pubmed
  4. Rogawski MA: Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents—toward an understanding of their favorable tolerability. Amino Acids. 2000;19(1):133-49. Pubmed
  5. Rammes G, Rupprecht R, Ferrari U, Zieglgansberger W, Parsons CG: The N-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci Lett. 2001 Jun 22;306(1-2):81-4. Pubmed
External Links
ResourceLink
KEGG CompoundC13736
PubChem Compound4054
PubChem Substance46506702
ChemSpider3914
BindingDB50062599
Therapeutic Targets DatabaseDAP000493
PharmGKBPA10364
Drug Product Database2260638
RxListhttp://www.rxlist.com/cgi/generic3/namenda.htm
Drugs.comhttp://www.drugs.com/cdi/memantine.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/cx1682.shtml
WikipediaMemantine
ATC CodesN06DX01
AHFS Codes
  • 28:92.00
PDB EntriesNot Available
FDA labelshow(102 KB)
MSDSshow(65.7 KB)
Interactions
Drug Interactions
Drug
AcetazolamidePossible increased levels of memantine
AmantadineIncreased risk of CNS adverse effects with this association
DiclofenamidePossible increased levels of memantine
KetamineIncreased risk of CNS adverse effects with this association
MethazolamidePossible increased levels of memantine
Sodium bicarbonatePossible increased levels of memantine
Food Interactions
  • Take without regard to meals.

Targets

1. Glutamate receptor ionotropic, NMDA 3A

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Glutamate receptor ionotropic, NMDA 3A Q8TCU5 Details

References:

  1. Smothers CT, Woodward JJ: Pharmacological characterization of glycine-activated currents in HEK 293 cells expressing N-methyl-D-aspartate NR1 and NR3 subunits. J Pharmacol Exp Ther. 2007 Aug;322(2):739-48. Epub 2007 May 14. Pubmed
  2. Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S, Sevarino KA, Nakanishi N, Tong G, Lipton SA, Zhang D: Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature. 2002 Feb 14;415(6873):793-8. Epub 2002 Jan 30. Pubmed
  3. Schrattenholz A, Soskic V: NMDA receptors are not alone: dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate-signalling. Curr Top Med Chem. 2006;6(7):663-86. Pubmed
  4. Foster AC, Kemp JA: Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17. Epub 2005 Dec 22. Pubmed
  5. Rogawski MA, Wenk GL: The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev. 2003 Fall;9(3):275-308. Pubmed

2. Glutamate receptor ionotropic, NMDA 2A

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Glutamate receptor ionotropic, NMDA 2A Q12879 Details

References:

  1. Chen HS, Lipton SA: Pharmacological implications of two distinct mechanisms of interaction of memantine with N-methyl-D-aspartate-gated channels. J Pharmacol Exp Ther. 2005 Sep;314(3):961-71. Epub 2005 May 18. Pubmed
  2. Maler JM, Esselmann H, Wiltfang J, Kunz N, Lewczuk P, Reulbach U, Bleich S, Ruther E, Kornhuber J: Memantine inhibits ethanol-induced NMDA receptor up-regulation in rat hippocampal neurons. Brain Res. 2005 Aug 9;1052(2):156-62. Pubmed
  3. Bresink I, Benke TA, Collett VJ, Seal AJ, Parsons CG, Henley JM, Collingridge GL: Effects of memantine on recombinant rat NMDA receptors expressed in HEK 293 cells. Br J Pharmacol. 1996 Sep;119(2):195-204. Pubmed
  4. Blanpied TA, Boeckman FA, Aizenman E, Johnson JW: Trapping channel block of NMDA-activated responses by amantadine and memantine. J Neurophysiol. 1997 Jan;77(1):309-23. Pubmed
  5. Rogawski MA, Wenk GL: The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev. 2003 Fall;9(3):275-308. Pubmed

3. Glutamate receptor ionotropic, NMDA 2B

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Glutamate receptor ionotropic, NMDA 2B Q13224 Details

References:

  1. Kashiwagi K, Masuko T, Nguyen CD, Kuno T, Tanaka I, Igarashi K, Williams K: Channel blockers acting at N-methyl-D-aspartate receptors: differential effects of mutations in the vestibule and ion channel pore. Mol Pharmacol. 2002 Mar;61(3):533-45. Pubmed
  2. Nakazato E, Kato A, Watanabe S: Brain but not spinal NR2B receptor is responsible for the anti-allodynic effect of an NR2B subunit-selective antagonist CP-101,606 in a rat chronic constriction injury model. Pharmacology. 2005 Jan;73(1):8-14. Epub 2004 Sep 27. Pubmed
  3. Maler JM, Esselmann H, Wiltfang J, Kunz N, Lewczuk P, Reulbach U, Bleich S, Ruther E, Kornhuber J: Memantine inhibits ethanol-induced NMDA receptor up-regulation in rat hippocampal neurons. Brain Res. 2005 Aug 9;1052(2):156-62. Pubmed
  4. Blanpied TA, Boeckman FA, Aizenman E, Johnson JW: Trapping channel block of NMDA-activated responses by amantadine and memantine. J Neurophysiol. 1997 Jan;77(1):309-23. Pubmed
  5. Rogawski MA, Wenk GL: The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev. 2003 Fall;9(3):275-308. Pubmed

4. 5-hydroxytryptamine receptor 3A

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 3A P46098 Details

References:

  1. Rammes G, Rupprecht R, Ferrari U, Zieglgansberger W, Parsons CG: The N-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci Lett. 2001 Jun 22;306(1-2):81-4. Pubmed

5. Alpha-7 nicotinic cholinergic receptor subunit

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Alpha-7 nicotinic cholinergic receptor subunit Q693P7 Details

References:

  1. Aracava Y, Pereira EF, Maelicke A, Albuquerque EX: Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons. J Pharmacol Exp Ther. 2005 Mar;312(3):1195-205. Epub 2004 Nov 2. Pubmed

6. D(2) dopamine receptor

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: agonist

Components

Name UniProt ID Details
D(2) dopamine receptor P14416 Details

References:

  1. Seeman P, Caruso C, Lasaga M: Memantine agonist action at dopamine D2High receptors. Synapse. 2008 Feb;62(2):149-53. Pubmed

7. Glutamate receptor ionotropic, NMDA 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: binder

Components

Name UniProt ID Details
Glutamate receptor ionotropic, NMDA 1 Q05586 Details

References:

  1. Kotermanski SE, Wood JT, Johnson JW: Memantine binding to a superficial site on NMDA receptors contributes to partial trapping. J Physiol. 2009 Oct 1;587(Pt 19):4589-604. doi: 10.1113/jphysiol.2009.176297. Epub 2009 Aug 17. Pubmed

Enzymes

1. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

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 2A6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2A6 P11509 Details

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

3. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

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. Solute carrier family 22 member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 22 member 2 O15244 Details

References:

  1. Busch AE, Karbach U, Miska D, Gorboulev V, Akhoundova A, Volk C, Arndt P, Ulzheimer JC, Sonders MS, Baumann C, Waldegger S, Lang F, Koepsell H: Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol. 1998 Aug;54(2):342-52. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on October 08, 2013 14:24