Glutamate 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.<unk>  is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors. By binding to the NMDA receptor with a higher affinity than Mg2+ ions,<unk>  is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. The low affinity, uncompetitive nature, and rapid off-rate kinetics of<unk>  at the level of the NMDA receptor-channel, however, preserves the function of the receptor at synapses, as it can still be activated by physiological release of glutamate following depolarization of the postsynaptic neuron. The interaction of<unk>  with NMDA receptors plays a major role in the symptomatic improvement that the drug produces in Alzheimer's disease. However, there is no evidence as yet that the ability of<unk>  to protect against NMDA receptor-mediated excitotoxicity has a disease-modifying effect in Alzheimer's, although this has been suggested in animal models.<unk> 's antagonism on NMDA receptors has aroused interest in repurposing it for mental illnesses such as bipolar disorder, considering the involvement of the glutamatergic system in the pathophysiology of mood disorders. Serotonin<unk>  acts as a non-competitive antagonist at the 5-HT3 receptor, with a potency similar to that for the NMDA receptor. Many 5-HT3 antagonists function as antiemetics, however the clinical significance of this serotonergic activity in the treatment of Alzheimer's disease is unknown. Cholinergic<unk>  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<unk>  is an antagonist at Alpha-7 nAChR, which may contribute to initial worsening of cognitive function during early<unk>  treatment. Alpha-7 nAChR upregulates quickly in response to antagonism, which could explain the cognitive-enhancing effects of chronic<unk>  treatment. 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. Dopamine<unk>  acts as an agonist at the dopamine D2 receptor with equal or slightly higher affinity than to the NMDA receptors. Sigmaergic<unk>  acts as an agonist at the σ1 receptor with a low affinity (Ki 2.6 μM). The consequences of this activity are unclear (as the role of sigma receptors in general is not yet that well understood). Due to this low affinity, therapeutic concentrations of<unk>  are most likely too low to have any sigmaergic effect as a typical therapeutic dose is 20 mg, however excessive doses of<unk>  taken for recreational purposes many times greater than prescribed doses may indeed activate this receptor.
Memantine
Rivastigmine
Donepezil
Nusinersen
Bromperidol decanoate
Perhexiline
Carbidopa/levodopa
Rilonacept