Memantine

HCID 4054CAS 19982-08-2

기본 정보

표준 SMILES
CC12CC3CC(C)(C1)CC(N)(C3)C2
InChIKey
BUGYDGFZZOZRHP-UHFFFAOYSA-N
분자식
C12H21N
평균 분자량
179.3 g/mol
단동위원소 질량
179.16739967

개요

Memantine is a primary aliphatic amine that is the 3,5-dimethyl derivative of 1-aminoadamantane. A low to moderate affinity uncompetitive (open-channel); NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels. It has a role as an antidepressant, an antiparkinson drug, a dopaminergic agent, a NMDA receptor antagonist and a neuroprotective agent. It is a primary aliphatic amine and a member of adamantanes. It is a conjugate base of a memantinium(1+). It derives from a hydride of an adamantane.

이름 및 식별자

우선 이름
Memantine
IUPAC
3,5-dimethyladamantan-1-amine

이름 및 동의어

memantine19982-08-23,5-dimethyladamantan-1-amine1-Amino-3,5-dimethyladamantaneMemantina3,5-Dimethyl-1-adamantanamineMemantinum1,3-Dimethyl-5-adamantanaminenemdatine3,5-Dimethyl-1-aminoadamantaneTricyclo[3.3.1.13,7]decan-1-amine, 3,5-dimethyl-DTXSID5045174
이름 더 보기
DRG-02673,5-Dimethyltricyclo(3.3.1.1(3,7))decan-1-amineW8O17SJF3TD-145NSC-7578431,3-Dimethyl-5-aminoadamantaneDTXCID3025174CHEBI:64312

데이터베이스 식별자

CAS
19982-08-2
PubChem CID
4054
DTXSID
DTXSID5045174
ChEMBL
CHEMBL807
ChEBI
CHEBI:64312
UNII
W8O17SJF3T
EC Number
690-724-9

물성

구조 계산 물성

XLogP
3.3
극성 표면적
26 Ų
수소 결합 공여자 수
1
수소 결합 수용자 수
1
회전 가능 결합 수
0
무거운 원자 수
13

실험 및 물리화학적 성질

Drugs · 2건

Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds

Pharmaceuticals

LogP · 3건

log Kow = 3.28

3.5

3.28

Color/FormOil
Solubility · 2건

soluble in water

4.55e-02 g/L

Human Drugs · 6건

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

Melting Point · 2건

White to off white fine powder. Crystals from alcohol/ether. MP: 290-295 °C, also reported as 290-295 °C. Soluble in water. /Memantine hydrochloride/

258 °C (hydrochloride salt)

안전 및 규제

GHS 분류

GHS Classification · 5건

This chemical does not meet GHS hazard criteria for 50% (1 of 2) of reports.

Warning

H302 (50%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 2 reports by companies from 2 notifications to the ECHA C&L Inventory.

유해성 정보

FDA Requirements · 1건

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including memantine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Memantine hydrochloride/

Toxic Combustion ProductsSpecial hazards arising from the substance or mixture: Carbon oxides, nitrogen oxides (NOx), Hydrogen chloride gas
Hazard Classes and CategoriesAcute Tox. 4 (50%)
Hazardous Reactivities and IncompatibilitiesIncompatible materials: Strong oxidizing agents

안전 및 보호

Fire Fighting Procedures · 2건

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Storage ConditionsConditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Keep in a dry place.
Cleanup Methods · 1건

ACCIDENTAL RELEASE MEASURES. Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapours, mist or gas.; Environmental precautions: Do not let product enter drains.; Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.

Disposal Methods · 1건

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Preventive Measures · 2건

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed.

Personal Protective Equipment (PPE) · 4건

Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Skin protection: Handle with gloves.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

독성 정보

TreatmentAs in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of urine. (L1712)
Interactions · 5건

Protein-bound Drugs: Because plasma protein binding of memantine is low (45%), a pharmacokinetic interaction with drugs that are highly protein bound (e.g., digoxin, warfarin) is unlikely.

Drugs Secreted by Renal Tubular Cationic Transport: Potential pharmacokinetic interaction (altered plasma concentrations of both drugs) when memantine is used with drugs secreted by the same renal cationic system (e.g., cimetidine, hydrochlorothiazide, metformin, nicotine, quinidine, ranitidine, triamterene). However, concomitant use of memantine with a fixed combination of hydrochlorothiazide and triamterene did not affect bioavailability of either memantine or triamterene, and maximum plasma concentrations and area under the plasma concentration-time curve (AUC) of hydrochlorothiazide decreased by only 20%. In addition, concomitant use of memantine with a fixed combination of glyburide and metformin hydrochloride did not affect the pharmacokinetics of memantine, metformin, or glyburide, and the hypoglycemic effects of the glyburide-metformin combination were not affected.

Alkalinizing Agents: Potential decreased memantine clearance with resulting increases in adverse effects when drug is used concomitantly with agents that increase urine pH (e.g., carbonic anhydrase inhibitors, sodium bicarbonate). Use with caution. Memantine clearance was decreased by approximately 80% at alkaline urine conditions (ie, pH 8).

Cholinesterase Inhibitors: Concomitant use of memantine with the acetylcholinesterase inhibitor donepezil did not affect the pharmacokinetics of either drug or substantially alter acetylcholinesterase inhibition by donepezil. In a 24-week clinical study in patients with moderate to severe Alzheimer's disease, adverse effects observed with combination therapy with memantine and donepezil were similar to those observed with donepezil alone. In vitro and animal studies indicate that memantine does not affect the reversible inhibition of acetylcholinesterase produced by donepezil, galantamine, or tacrine.

For more Interactions (Complete) data for MEMANTINE (9 total), please visit the HSDB record page.

Hepatotoxicity · 1건

In large placebo controlled trials, the rate of serum enzyme elevations during memantine therapy was similar to that in patients on placebo and no instances of clinically apparent liver injury were reported. Nevertheless, since its introduction into clinical use, memantine has been implicated in at least one report of clinically apparent hepatotoxicity. The time to onset was 3 weeks and the clinical syndrome was that of an acute cholestatic hepatitis which was mild-to-moderate in severity and rapidly reversible upon drug discontinuation (Case 1). Immunoallergic and autoimmune features were not present.

Environmental Fate · 3건

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 660(SRC), determined from a structure estimation method(2), indicates that memantine is expected to have very low mobility in soil(SRC). The estimated pKa of memantine is 10.7(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Memantine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.9X10-4 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2015).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 660(SRC), determined from a structure estimation method(2), indicates that memantine is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 10.7(3) indicates memantine will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water and moist soil surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 70(SRC), from its log Kow of 3.28(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Biodegradation data in water were not available(SRC, 2015).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), memantine, which has an estimated vapor pressure of 1.9X10-4 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase memantine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 4 hrs(SRC), calculated from its rate constant of 3.3X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Memantine does not contain chromophores that absorb at wavelengths >290 nm(4) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Adverse Effects · 1건

The most common adverse effects of memantine in clinical trials include dizziness, headache, confusion, diarrhea, and constipation. Additional adverse effects include fatigue, pain, hypertension, weight gain, hallucination, confusion, aggressive behavior, vomiting, abdominal pain, and urinary incontinence.

Exposure RoutesWell absorbed orally with a bioavailability of approximately 100%. Peak plasma concentrations are reached in 3-7 hours. Food has no effect on absorption.

규제 정보

FDA Requirements · 1건

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including memantine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Memantine hydrochloride/

화학 및 산업

약리 정보

ATC Code · 3건

N06DX01

N - Nervous system

QN - Nervous system

Protein BindingThe protein binding for memantine is about 45%.
Pharmacodynamics · 1건

**General effects** This drug inhibits calcium influx into cells that is normally caused by chronic NMDA receptor activation by glutamate. This leads to the improvement of Alzheimer's dementia symptoms, demonstrated by increased cognition and other beneficial central nervous system effects. **Effects on neuroplasticity** Like other NMDA receptor antagonists, memantine at high doses can reduce neuronal synaptic plasticity that is involved in learning and memory processes. At lower concentrations, which are normally used in the clinical setting, memantine can enhance neuronal synaptic plasticity in the brain, improve memory, and act as a neuroprotectant against the destruction of neurons caused by excitatory neurotransmitters. **Effect on various receptors** Memantine has demonstrated minimal activity for GABA, benzodiazepine, dopamine, adrenergic, histamine, and glycine receptors, as well as voltage-dependent Ca2+, Na+ or K+ channels. This drug has shown antagonist activity at the 5HT3 receptors. Laboratory studies suggest that memantine does not affect the reversible inhibition of the acetylcholinesterase normally caused by donepezil, galantamine, or tacrine.

Mechanism of Action · 5건

Continuous activation of the N-methyl-D-aspartate (NMDA) receptors in the central nervous system caused by _glutamate_ is thought to cause some of the Alzheimer's disease symptoms. This overactivation is thought to contribute to neurotoxicity due to the excitatory properties of glutamate. The pharmacological effect of memantine likely occurs via the drug's behavior as an uncompetitive (open-channel) NMDA receptor antagonist, preventing glutamate action on this receptor. Memantine has a preference for the NMDA receptor-operated cation channels. Despite these antagonist effects, memantine has not been proven to prevent or retard the neurodegeneration seen in patients diagnosed with Alzheimer’s disease.

In addition to exhibiting antagonists activity at the NMDA receptor, memantine exhibits antagonist activity at the type 3 serotonergic (5-HT3) receptor with a potency that appears to be similar to that at the NMDA receptor. Memantine also blocks the nicotinic acetylcholine receptor with a potency of about one-sixth to one-tenth that at the NMDA receptor. Memantine exhibits little or no affinity for gamma-aminobutyric acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, or glycine receptors or for voltage-dependent calcium, sodium, or potassium channels.

Memantine is a similar uncompetitive NMDA-receptor antagonist to MK-801 and phencyclidine (PCP), and it prevents nerve cell death induced by the ischemia which induces as excessive release of glutamate. These medicines act on an ion channel binding site similar to the magnesium ion binding site. However, MK-801 and PCP cause schizophrenic symptoms, so they are not being used as a therapeutic drug for Alzheimer's Disease. Memantine does not have those toxicities and does not stimulate acetylcholine release in the cerebral cortex. Although the mechanism of the difference from memantine and MK-801 has not been made clear yet, it seems that memantine is combined and released with the ion channel depending on electric potential in the same way as the magnesium ion.

As an uncompetitive inhibitor of the NMDA receptor, memantine, as with MK-801, does not block the binding of the neurotransmitter ,glutamate, to the receptor but rather blocks the ion current through the receptor channel that is activated by glutamate. ... Unlike such high affinity antagonist (MK-80), memantine blocks the NMDA receptor with relatively strong voltage dependence and rapid blocking/unblocking kinetics, dissociating from the NMDA receptors in response to membrane depolarization more readily than MK-801. ... Memantine is able to dissociate from the receptor in response to the strong, transient depolarizations that trigger physiological NMDA receptor activity, while blocking the receptor channels during the chronic, low level excitation that is thought to occur in neurodegenerative diseases such as Alzheimer's disease.

Memantine (Namenda) is prescribed as a treatment for moderate to severe Alzheimer's Disease. Memantine functions by blocking the NMDA receptor, but the key binding interactions between drug and receptor are not fully elucidated. To determine key binding interactions of memantine, we made side-by-side comparisons of IC(50) for memantine and amantadine, a structurally related drug, in the GluN1/GluN2B NMDA receptor. We identified hydrophobic binding pockets for the two methyl groups on memantine formed by the residues A645 and A644 on the third transmembrane helices of GluN1 and GluN2B, respectively. Moreover, we found that while adding two methyl groups to amantadine to produce memantine greatly improves affinity, adding a third methyl group to produce the symmetrical trimethylamantadine diminished affinity. Our results provide a better understanding of chemical-scale interactions between memantine and the NMDA channel, which will potentially benefit the development of new drugs for neurodegenerative diseases involving NMDA receptors.

Biological Half-Life · 2건

The terminal elimination half-life of memantine ranges from 60 to 80 hours in humans. Following administration of a single oral dose of 10 mg/kg memantine in rats, the elimination half-life was 2.36 ± 0.20 hours. Following a single intravenous dose of 2 mg/kg in rats, the elimination half-life was 2.28 ± 0.48 hours.

The terminal elimination half-life of memantine is approximately 60-80 hours.

Metabolism/Metabolites · 4건

This drug is partially metabolized in the liver. The hepatic CYP450 enzyme system does not majorly contribute to the metabolism of this drug.

Memantine undergoes partial hepatic metabolism. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine.

The hepatic microsomal cytochrome P-450 (CYP) isoenzyme system does not play a substantial role in the metabolism of memantine.

Excreted largely unchanged. About 20% is metabolized to 1-amino-3-hydroxymethyl-5-methyl-adamantane and 3-amino-1-hydroxy-5,7-dimethyl-adamantane. Route of Elimination: Memantine 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 Life: 60-100 hours

용도 및 제조

Uses · 5건

MEDICATION

MEDICATION (VET)

Antiparkinson Agents; Dopamine Agents; Excitatory Amino Acid Antagonists

Use (kg; approx.) in Germany (2009): >500

For the treatment of moderate to severe dementia of the Alzheimer's type.

Methods of Manufacturing/Preparation/ of the free base and hydrochloride: J. Mills, E. Krumkalns, USA 3391142 (1968 to Lilly).
Formulations/PreparationsTable: Memantine Hydrochloride Preparations [Table#6915]
Use ClassificationPharmaceuticals
General Manufacturing Information · 2건

NMDA-receptor antagonist; derivative of adamantane.

Information available in 2005 indicated that Memantine hydrochloride was used in the manufacture of pharmaceutical preparations in the following countries: Argentina, Australia, Austria, Belgium, Colombia, Denmark, Dominican Republic, El Salvador, Finland, France, Germany, Guatemala, Honduras, Hungary, Ireland, Luxembourg, Norway, Panama, Russian Federation, Spain, Switzerland, United Kingdom, United States (1,2)

관련 반응

10건

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