Memantine

Oral🕒 Plan

Route dataPsychonautWiki

🧬 Receptor activityPHDC

Mechanism of actionPHDM

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.

PharmacodynamicsPHDM

**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.

Pharmacokinetics

External links