After a single injection of cholinergic neurotoxin ethylcholine aziridinium (AF64A, 3 nmol intracerebroventricularly (i.c.v.)), rats failed to perform the tasks in the active avoidance (learning and retention paradigms) and water maze tests. N-Acetylserotonin (NAS), melatonin and their newly synthesized derivatives, CA-15 and CA-18, (0.3-3.0 mg/kg daily for 12-14 days) reversed the effect of AF64A in a dose-dependent manner with CA-18 being the most active. Melatonin and NAS caused sedation absent in CA-18-treated rats. The studied compounds (25-500 microM for 72 hr) protected against beta-amyloid peptide (beta AP) fragment 25-35-induced neurotoxicity in cerebellar granule cell culture. Our results suggest that neuroprotecting properties of these compounds might mediate their cognition-enhancing effects. The results obtained warrant the further search for the novel types of safe neuroprotectors among the synthetic NAS/melatonin derivatives.
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.
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