Memantine

Memantine

Systematic (IUPAC) name
3,5-dimethyltricyclo[3.3.1.13,7]decan-1amine or 3,5-dimethyladamantan-1-amine
Clinical data
Trade names	Namenda
AHFS/Drugs.com	monograph
MedlinePlus	a604006
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	B2 (Au), B (U.S.)
Legal status	S4 (Au), POM (UK), ℞-only (U.S.)
Routes	Oral
Pharmacokinetic data
Bioavailability	~100%
Metabolism	Hepatic (<10%)
Half-life	60–100 hours
Excretion	Renal
Identifiers
CAS number	19982-08-2 Y
ATC code	N06DX01
PubChem	CID 4054
DrugBank	DB01043
ChemSpider	3914 Y
UNII	W8O17SJF3T Y
KEGG	D08174 Y
ChEMBL	CHEMBL807 Y
Chemical data
Formula	C12H21N
Mol. mass	179.3 g/mol
SMILES	eMolecules & PubChem
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 Y Key:BUGYDGFZZOZRHP-UHFFFAOYSA-N Y
Y (what is this?)  (verify)

Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking NMDA glutamate receptors. It was first synthesized by Eli Lilly and Company in 1968. Memantine is marketed under the brands Axura and Akatinol by Merz, Namenda by Forest, Ebixa and Abixa by Lundbeck and Memox by Unipharm. Despite years of research, there is little evidence of effect in mild to moderate Alzheimer's disease.^[1]

Medical use

Memantine is approved for treatment of moderate to severe Alzheimer's disease,^[2] and has now received a limited recommendation by the UK's National Institute for Clinical Excellence for patients who fail other treatment options.^[3] Within the new guidance memantine is recommended as an option for managing Alzheimer’s disease for people with: moderate Alzheimer’s disease who are intolerant of or have a contraindication to AChE (acetylcholinesterase) inhibitors or those with severe Alzheimer’s disease.

Memantine has been associated with a moderate decrease in clinical deterioration^[4] with only a small positive effect on cognition, mood, behaviour, and the ability to perform daily activities in moderate to severe Alzheimer's disease.^[5] There does not appear to be any benefit in mild disease.^[1]

Adverse effects

Memantine is, in general, well-tolerated.^[5] Common adverse drug reactions (≥1% of patients) include confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common adverse effects include vomiting, anxiety, hypertonia, cystitis, and increased libido.^[4][6] It has been reported to induce reversible neurological impairment in multiple sclerosis patients, which led to the halt of an ongoing clinical trial.^[7][8] Though exceedingly rare, extrapyramidal side-effects (such as dystonic reactions, etc.) may occur, in particular, in the younger population.^{[citation needed]}

A recent study demonstrates therapeutically-relevant doses of memantine in the mouse can lead to disruption of cognitive flexibility.^[9]

Biochemistry

The drug belongs to a class of drugs called NMDA receptor antagonists, which reduce certain types of brain activity by binding to NMDA receptors on brain cells and blocking the activity of the neurotransmitter glutamate. At normal levels, glutamate aids in memory and learning, but if levels are too high, glutamate appears to overstimulate nerve cells, killing them through excitotoxicity.

Pharmacology

Glutamatergic (NMDA receptor)

A dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is hypothesized to be involved in the etiology of Alzheimer's disease. Targeting the glutamatergic system, specifically NMDA receptors, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic system.^[10]

Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors.^[11][12][13] By binding to the NMDA receptor with a higher affinity than Mg²⁺ ions, memantine is able to inhibit the prolonged influx of Ca²⁺ ions, which forms the basis of neuronal excitotoxicity. The low affinity and rapid off-rate kinetics of memantine at the level of the NMDA receptor-channel, however, preserves the physiological function of the receptor, as it can still be activated by the relatively high concentrations of glutamate released following depolarization of the presynaptic neuron.^{[14][15][16][17][18][19][20][21]} The interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement that the drug produces in Alzheimer's disease. Moreover, there is no evidence as yet that the ability of memantine to protect against NMDA receptor-mediated excitotoxicity has a disease-modifying effect in Alzheimer's, although this has been suggested in animal models.^[16]

Serotonergic (5-HT₃ receptor)

Memantine acts as a non-competitive antagonist at the 5-HT3 receptor, with a potency similar to that for the NMDA receptor.^[22] The clinical significance of this serotonergic activity in the treatment of Alzheimer's disease is unknown.

Cholinergic (nicotinic acetylcholine receptor)

Memantine acts as a non-competitive antagonist at different neuronal nicotinic acetylcholine receptors (nAChRs) at potencies possibly similar to the NMDA and 5-HT3 receptors, but this is difficult to ascertain with accuracy because of the rapid desensitization of nAChR responses in these experiments. It can be noted that memantine is an antagonist at alpha-7 nAChR, which may contribute to initial worsening of cognitive function during early memantine treatment. Alpha-7 nAChR upregulates quickly in response to antagonism, which could explain the cognitive-enhancing effects of chronic memantine treatment.^[20][23][24] It has been shown that the number of nicotinic receptors in the brain are reduced in Alzheimer's disease, even in the absence of a general decrease in the number of neurons, and nicotinic receptor agonists are viewed as interesting targets for anti-Alzheimer drugs.^[25] Consequently, this may also suggest that administration of nicotine itself may act against the effects of Alzheimer's disease. In fact a recent small double blind placebo controlled randomized trial published in the Journal Neurology demonstrated a significant benefit from use of 15mg nicotine patches in non-smoking elderly patients with mild cognitive impairment. The small sample sizes suggest that the effect size is substantial due to the limited statistical power inherent in a small N trial. (see : http://www.ncbi.nlm.nih.gov/pubmed/22232050)

Dopaminergic (D₂ receptor)

Memantine acts as an agonist at the dopamine D₂ receptor.^[26]

History

Memantine was first synthesized and patented by Eli Lilly and Company in 1968 (as cited in the Merck Index), and then developed by Merz in collaboration with Neurobiological Technologies, Inc. and licensed to Forest for the U.S. and Lundbeck for selected European and international markets.

Sales of the drug reached $1.2 billion for 2010.

Research

Memantine is also being tested for generalized anxiety disorder, epilepsy, opioid dependence, systemic lupus erythematosus, depression, obsessive compulsive disorder, Tourette Syndrome, problem gambling, attention-deficit hyperactivity disorder (ADHD),^[27] glaucoma, tinnitus, neuropathic pain including Complex Regional Pain Syndrome,^[28] pervasive developmental disorders, HIV associated dementia,^[29] nystagmus,^[30] multiple sclerosis^[7], autism^[31], migraine.^[32] and amyotrophic lateral sclerosis^[33].

See also

• NMDA receptor antagonist

References

Further reading

• Lipton SA (2005). "The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: low-affinity, uncompetitive antagonism". Current Alzheimer research 2 (2): 155–65. doi:10.2174/1567205053585846. PMID 15974913. 

External links

• Namenda website