Neuroprotective and biobehavioral properties of a series of novel open chain MK‐801 analogs, as well as their structure‐activity relationships have been investigated. Three groups of compounds were synthesized: monobenzylamino, benzhydrylamino, and dibenzylamino (DBA) analogs of MK‐801. It was revealed that DBA analogs exhibit pronounced glutamate‐induced calcium uptake blocking properties and anti‐NMDA activity. The hit compound of DBA series, NT‐1505, was investigated for its ability to improve cognition functions in animal model of Alzheimer's disease type dementia, simulated by treating animals with cholinotoxin AF64A. The results from an active avoidance test and a Morris water maze test showed that experimental animals, treated additionally with NT‐1505, exhibited much better learning ability and memory than the control group (AF64A treated) and close to that of the vehicle group of animals (treated with physiological solution). Study of NT‐1505 influence on locomotor activity revealed that it is characterized by a spectrum of behavioral activity radically different from that of MK‐801, and in contrast to the latter one does not produce any psychotomimetic side effects in the therapeutically significant dose interval. The computed docking of MK‐801 and its flexible analogs on the NMDA receptor elucidated the crucial role of the hydrogen bond formed between these compounds and the asparagine residue for magnesium binding in the NMDA receptor. It was suggested that strong hydrophobic interaction between MK‐801 and the hydrophobic pocket in the NMDA receptor‐channel complex determines much higher irreversibility of this adduct compared to the intermediates formed between this site and Mg ions or flexible DBA derivatives, which might explain the absence of PCP‐like side effects of the latter compounds.

We studied the effect of muramyl dipeptides on postsynaptic GABA, NMDA, and AMPA receptors and presynaptic NMDA receptors. L,D-Dipeptide more potently than L,L-dipeptide inhibited postsynaptic NMDA receptors, potentiated GABA and AMPA receptors, and inhibited (45)Ca(2+) uptake in synaptosomes from of rat brain cortex. Our results indicate that muramyl dipeptides modulate function of glutamate and GABA receptors.

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The aqueous extract of blueberry leaves inhibits the glutamate-induced Ca2+ influx into the synaptosomes of rat brain neurons and the IC50 value of this process is close to the IC50 for MK-801, a well-known noncompetitive antagonist of glutamate NMDA subtype receptors. The aqueous extract of blueberry leaves protected the cultured neurons of the rat cerebral cortex from the neurotoxic effect of glutamate, and the inhibition intensity depended on the incubation time with the extract.

The effect of interleukin-1beta on presynaptic NMDA receptors was evaluated by studying NMDA-induced 45Ca2+ uptake by synaptosomes from rat brain cortex. Interleukin-1beta inhibited 45Ca2+ uptake by synaptosomes. Our results indicate that interleukin-1beta modulates presynaptic NMDA receptors and is probably involved in the regulation of synaptic transmission in the central nervous system.