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Identification
Name Amantadine
Accession Number DB00915 (APRD00787)
Type small molecule
Groups approved
Description

An antiviral that is used in the prophylactic or symptomatic treatment of influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. The mechanisms of its effects in movement disorders are not well understood but probably reflect an increase in synthesis and release of dopamine, with perhaps some inhibition of dopamine uptake. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • 1-aminoadamantane
  • Adamantamine
  • Adamantanamine
  • Adamantylamine
  • Amantadine Base
  • Amantadine HCL
  • Amantadine Hydrochloride
  • Amantidine
  • Aminoadamantane
Brand names
  • Endantadine
  • Gen-Amantadine
  • Mantadine
  • Pk-Merz
  • Symadine
  • Symmetrel
Brand name mixtures Not Available
Categories
  • Antiviral Agents
  • Dopamine Agents
  • Antiparkinson Agents
  • Analgesics, Non-Narcotic
CAS number 768-94-5
Weight Average: 151.2487
Monoisotopic: 151.136099549
Chemical Formula C10H17N
InChI Key InChIKey=DKNWSYNQZKUICI-UHFFFAOYSA-N
InChI
InChI=1S/C10H17N/c11-10-4-7-1-8(5-10)3-9(2-7)6-10/h7-9H,1-6,11H2
Plain Text
IUPAC Name
adamantan-1-amine
SMILES
NC12CC3CC(CC(C3)C1)C2
Plain Text
Mass Spec show (7.7 KB)
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication For the chemoprophylaxis, prophylaxis, and treatment of signs and symptoms of infection caused by various strains of influenza A virus. Also for the treatment of parkinsonism and drug-induced extrapyramidal reactions.
Pharmacodynamics Amantadine is an antiviral drug which also acts as an antiparkinson agent, for which it is usually combined with L-DOPA when L-DOPA responses decline (probably due to tolerance). It is a derivate of adamantane, like a similar drug rimantadine. The mechanism of action of amantadine in the treatment of Parkinson's disease and drug-induced extrapyramidal reactions is not known. It has been shown to cause an increase in dopamine release in the animal brain, and does not possess anticholinergic activity.
Mechanism of action The mechanism of its antiparkinsonic effect is not fully understood, but it appears to be releasing dopamine from the nerve endings of the brain cells, together with stimulation of norepinephrine response. It also has NMDA receptor antagonistic effects. The antiviral mechanism seems to be unrelated. The drug interferes with a viral protein, M2 (an ion channel), which is needed for the viral particle to become "uncoated" once it is taken inside the cell by endocytosis.
Absorption Amantadine is well absorbed orally from the gastrointestinal tract.
Volume of distribution
  • 3 to 8 L/kg [healthy subjects]
Protein binding Approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0 µg/mL.
Metabolism

No appreciable metabolism, although negligible amounts of an acetyl metabolite have been identified.
Route of elimination It is primarily excreted unchanged in the urine by glomerular filtration and tubular secretion.
Half life Mean half-lives ranged from 10 to 14 hours, however renal function impairment causes a severe increase in half life to 7 to 10 days.
Clearance
  • 0.2 – 0.3 L/hr/kg
  • 0.10 +/- 0.04 L/hr/kg [healthy, elderly male]
Toxicity Deaths have been reported from overdose with amantadine. The lowest reported acute lethal dose was 2 grams. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress (including ARDS) have been reported. Renal dysfunction including increased BUN, decreased creatinine clearance and renal insufficiency can occur. Central nervous system effects that have been reported include insomnia, anxiety, aggressive behavior, hypertonia, hyperkinesia, tremor, confusion, disorientation, depersonalization, fear, delirium, hallucination, psychotic reactions, lethargy, somnolence and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has also been observed in cases where a drug overdose has occurred.
Affected organisms
  • Humans and other mammals
  • Various viruses
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Actavis totowa llc
  • Banner pharmacaps inc
  • Sandoz inc
  • Usl pharma inc
  • Watson laboratories inc
  • Solvay pharmaceuticals
  • Endo pharmaceuticals inc
  • Actavis mid atlantic llc
  • Carolina medical products co
  • Hi tech pharmacal co inc
  • Mikart inc
  • Pharmaceutical assoc inc div beach products
  • Silarx pharmaceuticals inc
  • Teva pharmaceuticals usa
  • Vintage pharmaceuticals llc
  • Wockhardt eu operations (swiss) ag
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Syrup Oral
Prices
Unit description Cost Unit
Symmetrel 50 mg/5ml Syrup 480ml Bottle 151.46 USD bottle
Amantadine hcl powder 6.7 USD g
Symmetrel 100 mg tablet 1.45 USD tablet
Amantadine HCl 100 mg tablet 1.37 USD tablet
Amantadine 100 mg tablet 1.32 USD tablet
Amantadine HCl 100 mg capsule 0.78 USD capsule
Mylan-Amantadine 100 mg Capsule 0.54 USD capsule
Pms-Amantadine Hydrochloride 100 mg Capsule 0.54 USD capsule
Amantadine HCl 50 mg/5ml Syrup 0.16 USD ml
Pms-Amantadine Hydrochloride 10 mg/ml Syrup 0.09 USD ml
Patents Not Available
Properties
State solid
Melting point 180 oC
Experimental Properties
Property Value Source
water solubility 6290 mg/L (freely soluble) PhysProp
logP 2.3 PhysProp
Predicted Properties
Property Value Source
water solubility 8.46e-02 g/l ALOGPS
logP 2.53 ALOGPS
logP 1.4659475483333333 ChemAxon Molconvert
logS -3.25 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 1 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 26.02 ChemAxon Molconvert
rotatable bond count 0 ChemAxon Molconvert
refractivity 45.535599999999995 ChemAxon Molconvert
polarizability 17.917499069606556 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Compound C06818 Link_out
ChEBI 2618 Link_out
ChEMBL 2618 Link_out
Therapeutic Targets Database DAP000781 Link_out
PharmGKB PA448360 Link_out
Drug Product Database 2262649 Link_out
RxList http://www.rxlist.com/cgi/generic3/amantadine.htm Link_out
Drugs.com http://www.drugs.com/cdi/amantadine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Amantadine Link_out
ATC Codes
  • N04BB01
AHFS Codes
  • 08:18.04
PDB Entries Not Available
FDA label show (196.8 KB)
MSDS show (73.9 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Avoid alcohol.
  • Take without regard to meals.
Targets

1. Matrix protein 2

Pharmacological action: yes
Actions: inhibitor

Forms a highly low-pH gated proton-selective channel. When the environmental pH is lower than a threshold, the M2 channel is activated and selectively transports protons across the membrane from the extracellular side to the cytoplasmic side. Crucial for the uncoating process. When the virion is internalized into the endosome, the channel acidifies the virion's interior, promoting the dissociation of matrix protein 1 (M1) from the ribonucleoprotein (RNP) thus allowing the transport of the RNP from the virion into the cell's nucleus. Also plays a role in viral proteins secretory pathway. Elevates the intravesicular pH of normally acidic compartments, such as trans-Golgi network, preventing newly formed hemagglutinin from premature switching to the fusion-active conformation

Organism class: viral
UniProt ID: P21430 Link_out
Gene: M
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wang C, Takeuchi K, Pinto LH, Lamb RA: Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block. J Virol. 1993 Sep;67(9):5585-94. Pubmed
  2. Jing X, Ma C, Ohigashi Y, Oliveira FA, Jardetzky TS, Pinto LH, Lamb RA: Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10967-72. Epub 2008 Jul 31. Pubmed
  3. Wang J, Cady SD, Balannik V, Pinto LH, DeGrado WF, Hong M: Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus. J Am Chem Soc. 2009 Jun 17;131(23):8066-76. Pubmed
  4. Beigel J, Bray M: Current and future antiviral therapy of severe seasonal and avian influenza. Antiviral Res. 2008 Apr;78(1):91-102. Epub 2008 Feb 4. Pubmed
  5. Lear JD: Proton conduction through the M2 protein of the influenza A virus; a quantitative, mechanistic analysis of experimental data. FEBS Lett. 2003 Sep 18;552(1):17-22. Pubmed
  6. Salom D, Hill BR, Lear JD, DeGrado WF: pH-dependent tetramerization and amantadine binding of the transmembrane helix of M2 from the influenza A virus. Biochemistry. 2000 Nov 21;39(46):14160-70. Pubmed

2. Glutamate [NMDA] receptor subunit 3A

Pharmacological action: yes
Actions: antagonist

NMDA receptor subtype of glutamate-gated ion channels with reduced single-channel conductance, low calcium permeability and low voltage-dependent sensitivity to magnesium. Mediated by glycine. May play a role in the development of dendritic spines. May play a role in PPP2CB-NMDAR mediated signaling mechanism

Organism class: human
UniProt ID: Q8TCU5 Link_out
Gene: GRIN3A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Blanpied TA, Clarke RJ, Johnson JW: Amantadine inhibits NMDA receptors by accelerating channel closure during channel block. J Neurosci. 2005 Mar 30;25(13):3312-22. Pubmed
  2. Hesselink MB, De Boer AG, Breimer DD, Danysz W: Adaptations of NMDA and dopamine D2, but not of muscarinic receptors following 14 days administration of uncompetitive NMDA receptor antagonists. J Neural Transm. 1999;106(5-6):409-21. Pubmed

3. D(2) dopamine receptor

Pharmacological action: yes
Actions: agonist

This is one of the five types (D1 to D5) of receptors for dopamine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase

Organism class: human
UniProt ID: P14416 Link_out
Gene: DRD2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Tomitaka S, Hashimoto K, Narita N, Minabe Y, Tamura A: Amantadine induces c-fos in rat striatum: reversal with dopamine D1 and NMDA receptor antagonists. Eur J Pharmacol. 1995 Oct 16;285(2):207-11. Pubmed
  2. Ameri A: Effects of the Aconitum alkaloid songorine on synaptic transmission and paired-pulse facilitation of CA1 pyramidal cells in rat hippocampal slices. Br J Pharmacol. 1998 Oct;125(3):461-8. Pubmed
  3. Hirose G: Drug induced parkinsonism: A review. J Neurol. 2006 Aug;253 Suppl 3:iii22-iii24. doi:10.1007/s00415-006-3004-8
  4. Hesselink MB, De Boer AG, Breimer DD, Danysz W: Adaptations of NMDA and dopamine D2, but not of muscarinic receptors following 14 days administration of uncompetitive NMDA receptor antagonists. J Neural Transm. 1999;106(5-6):409-21. Pubmed
  5. Cousins MS, Carriero DL, Salamone JD: Tremulous jaw movements induced by the acetylcholinesterase inhibitor tacrine: effects of antiparkinsonian drugs. Eur J Pharmacol. 1997 Mar 19;322(2-3):137-45. Pubmed
Enzymes

1. Aromatic-L-amino-acid decarboxylase

Actions: inducer

Catalyzes the decarboxylation of L-3,4- dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine

UniProt ID: P20711 Link_out
Gene: DDC Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Li XM, Juorio AV, Qi J, Boulton AA: Amantadine increases aromatic L-amino acid decarboxylase mRNA in PC12 cells. J Neurosci Res. 1998 Aug 15;53(4):490-3. Pubmed
  2. Fisher A, Biggs CS, Starr MS: Effects of glutamate antagonists on the activity of aromatic L-amino acid decarboxylase. Amino Acids. 1998;14(1-3):43-9. Pubmed

2. Amine oxidase [flavin-containing] B

Actions: inhibitor

Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. MAOB preferentially degrades benzylamine and phenylethylamine

UniProt ID: P27338 Link_out
Gene: MAOB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wesemann W, Ekenna O: Effect of 1-aminoadamantanes on the MAO activity in brain, liver, and kidney of the rat. Arzneimittelforschung. 1982;32(10):1241-3. Pubmed
Transporters

1. Solute carrier family 22 member 2

Actions: inhibitor

Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creatinine, amantadine, memantine, acriflavine, 4-[4-(dimethylamino)-styryl]-N-methylpyridinium ASP, amiloride, metformin, N-1-methylnicotinamide (NMN), tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, cisplatin and oxaliplatin. Cisplatin may develop a nephrotoxic action. Transport of creatinine is inhibited by fluoroquinolones such as DX-619 and LVFX. This transporter is a major determinant of the anticancer activity of oxaliplatin and may contribute to antitumor specificity

UniProt ID: O15244 Link_out
Gene: SLC22A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Urakami Y, Akazawa M, Saito H, Okuda M, Inui K: cDNA cloning, functional characterization, and tissue distribution of an alternatively spliced variant of organic cation transporter hOCT2 predominantly expressed in the human kidney. J Am Soc Nephrol. 2002 Jul;13(7):1703-10. Pubmed
  2. 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
  3. Goralski KB, Lou G, Prowse MT, Gorboulev V, Volk C, Koepsell H, Sitar DS: The cation transporters rOCT1 and rOCT2 interact with bicarbonate but play only a minor role for amantadine uptake into rat renal proximal tubules. J Pharmacol Exp Ther. 2002 Dec;303(3):959-68. Pubmed
  4. Ishiguro N, Saito A, Yokoyama K, Morikawa M, Igarashi T, Tamai I: Transport of the dopamine D2 agonist pramipexole by rat organic cation transporters OCT1 and OCT2 in kidney. Drug Metab Dispos. 2005 Apr;33(4):495-9. Epub 2005 Jan 7. Pubmed

2. Solute carrier family 22 member 1

Actions: inhibitor

Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN), 4-(4-(dimethylamino)styryl)- N-methylpyridinium (ASP), the endogenous compounds choline, guanidine, histamine, epinephrine, adrenaline, noradrenaline and dopamine, and the drugs quinine, and metformin. The transport of organic cations is inhibited by a broad array of compounds like tetramethylammonium (TMA), cocaine, lidocaine, NMDA receptor antagonists, atropine, prazosin, cimetidine, TEA and NMN, guanidine, cimetidine, choline, procainamide, quinine, tetrabutylammonium, and tetrapentylammonium. Translocates organic cations in an electrogenic and pH-independent manner. Translocates organic cations across the plasma membrane in both directions. Transports the polyamines spermine and spermidine. Transports pramipexole across the basolateral membrane of the proximal tubular epithelial cells. The choline transport is activated by MMTS. Regulated by various intracellular signaling pathways including inhibition by protein kinase A activation, and endogenously activation by the calmodulin complex, the calmodulin- dependent kinase II and LCK tyrosine kinase

UniProt ID: O15245 Link_out
Gene: SLC22A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Bednarczyk D, Ekins S, Wikel JH, Wright SH: Influence of molecular structure on substrate binding to the human organic cation transporter, hOCT1. Mol Pharmacol. 2003 Mar;63(3):489-98. Pubmed
  2. Zhang L, Schaner ME, Giacomini KM: Functional characterization of an organic cation transporter (hOCT1) in a transiently transfected human cell line (HeLa). J Pharmacol Exp Ther. 1998 Jul;286(1):354-61. Pubmed
  3. Goralski KB, Lou G, Prowse MT, Gorboulev V, Volk C, Koepsell H, Sitar DS: The cation transporters rOCT1 and rOCT2 interact with bicarbonate but play only a minor role for amantadine uptake into rat renal proximal tubules. J Pharmacol Exp Ther. 2002 Dec;303(3):959-68. Pubmed
  4. Ishiguro N, Saito A, Yokoyama K, Morikawa M, Igarashi T, Tamai I: Transport of the dopamine D2 agonist pramipexole by rat organic cation transporters OCT1 and OCT2 in kidney. Drug Metab Dispos. 2005 Apr;33(4):495-9. Epub 2005 Jan 7. Pubmed

3. Multidrug resistance protein 1

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, Polli JW: Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharmacol Exp Ther. 2002 Dec;303(3):1029-37. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on September 22, 2011 11:56

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.