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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
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 KeyInChIKey=BUGYDGFZZOZRHP-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
    1-amino-3-hydroxymethyl-5-methyl-adamantaneDetails
    Memantine
      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 solubility4.55e-02 g/lALOGPS
      logP3.31ALOGPS
      logP2.07ChemAxon
      logS-3.6ALOGPS
      pKa (strongest basic)10.7ChemAxon
      physiological charge1ChemAxon
      hydrogen acceptor count1ChemAxon
      hydrogen donor count1ChemAxon
      polar surface area26.02ChemAxon
      rotatable bond count0ChemAxon
      refractivity54.49ChemAxon
      polarizability21.82ChemAxon
      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.

      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

      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

      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

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