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QuickView for Amantadine (compound)

Summary
General Info

PubChem

PubChem Compound 124108

Name:	Amantadine
PubChem Compound ID:	124108
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.
Molecular formula:	C₂₀H₃₆N₂O₄S
Molecular weight:	400.577 g/mol
Synonyms:	EINECS 250-604-5; Tricyclo(3.3.1.1(3,7))decan-1-amine, sulfate (2:1); 31377-23-8; Amantadine sulphate (INNM)

DrugBank

Identification

Name:	Amantadine
Name (isomeric):	DB00915
Drug Type:	small molecule
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.
Synonyms:	Adamantylamine; Adamantanamine; Amantadine HCL; 1-aminoadamantane; Amantidine; Amantadine Base; Aminoadamantane; Amantadine Hydrochloride; Adamantamine
Brand:	Symmetrel, Pk-Merz, Endantadine, Gen-Amantadine, Symadine, Mantadine
Category:	Analgesics, Non-Narcotic, Antiparkinson Agents, Dopamine Agents, Antiviral Agents
CAS number:	768-94-5

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.
Pharmacology:	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 extrapyrami... show more » 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. show less «
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 ... show more » 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. show less «
Absorption:	Amantadine is well absorbed orally from the gastrointestinal tract.
Protein binding:	Approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0 µg/mL.
Biotransformation:	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:	Various viruses\|\|Humans and other mammals

Interactions

Food interaction:

Avoid alcohol.

Take without regard to meals.

Drug interaction:

Paliperidone	The atypical antipsychotic agent, paliperidone, may decrease the therapeutic effect of the anti-Parkinson's agent, amantadine. This interaction may be due to the dopamine antagonist properties of paliperidone. Consider an alternate antipsychotic in those with Parkinson's disease or consider using clozapine or quetiapine if an atypical antipsychotic is necessary.
Donepezil	Possible antagonism of action
Ziprasidone	The atypical antipsychotic, ziprasidone, may antagonize the effect of the dopamine agonist, amantadine. Consider alternate therapy or monitor for worsening of movement disorder.
Thiothixene	Thiothixene may antaonize the effects of the anti-Parkinsonian agent, Amantadine. Consider alternate therapy or monitor for decreased effects of both agents.
Rivastigmine	Possible antagonism of action

Targets

Matrix protein 2

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

UniProt ID:

P21430

Gene:

Actions:

inhibitor

References:

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.
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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.
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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.
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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.
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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.
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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.
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Glutamate [NMDA] receptor subunit 3A

D(2) dopamine receptor

Enzymes

Aromatic-L-amino-acid decarboxylase

Amine oxidase [flavin-containing] B

Transporters

Solute carrier family 22 member 2

Solute carrier family 22 member 1

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

Gene:

SLC22A1

Actions:

inhibitor

References:

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.
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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.
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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.
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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.
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Multidrug resistance protein 1