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Dimebon, launched earlier in Russia as an antihistamine drug, was evaluated as a representative of a new generation of anti-Alzheimer's drugs that have two beneficial actions: (1) to alleviate symptoms, and (2) to prevent progression of the disease. The drug demonstrated cognition and memory-enhancing properties in the active avoidance test in rats treated with the neurotoxin AF64A, which selectively destroys cholinergic neurons. Dimebon protected neurons in the cerebellum cell culture against the neurotoxic action of beta-amyloid fragment (A beta 25-35, EC50 = 25 microM). In vitro, Dimebon displayed Ca(2+)-blocking properties (IC50 = 57 microM, on isolated rat ileum intestine) and pronounced anticholinesterase activity (IC50 = 7.9 microM and 42 microM for butyrylcholine esterase and acetylcholine esterase, respectively). It also exhibited strong anti-NMDA activity in the prevention of NMDA-induced seizures in mice (EC50 = 42 +/- 6 mg/kg i.p.). A beneficial effect of Dimebon in the therapy of Alzheimer's disease was demonstrated in a pilot clinical trial performed in the Moscow Center of Gerontology. Fourteen patients who participated in the trial were evaluated for their state of personality and for the severity of the disease. The evaluation included orientation (space, place, time, and patient personality), memory for the past and present, life in present, speech, irritability, and so forth. During and after the eight-week therapy with Dimebon, cognitive and self-service functions of patients improved significantly, and psychopathic symptoms, anxiety, depression, tearfulness, and headache were substantially diminished. The results of these studies suggest Dimebon as a new candidate for the therapy of Alzheimer's-like disorders.

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.

It is generally accepted that antioxidant properties of melatonin significantly contribute to its antiaging effect. Antioxidant effects of N-acetylserotonin (NAS), a melatonin precursor and metabolite, might predict its antiaging action as well. The antiaging effect of NAS was studied in female retired breeders and male C3H mice. Both NAS and melatonin administered with drinking water prolonged life span in male animals by about 20% versus control animals (p < 0.01) but did not affect the life span of female mice. Antioxidative activity was evaluated by determining the malonaldehyde + 4-hydroxynonenal (MDA + 4-HNE) and cellular glutathion peroxidase (GPx) levels in male, 11-month-old, C57Bl/6J mice with very limited (if any) capacity to convert pineal NAS into melatonin. NAS increased the antioxidant capacity of kidney. Both NAS and melatonin (four weeks daily i.p. injections) increased the antioxidant capacity of brain as demonstrated by decreased MDA + 4-HNE and increased GPx levels. NAS-treated C57Bl/6J mice experienced a weight loss of 9%, whereas the saline and melatonin groups only 3%. NAS- and melatonin-treated animals had healthy and luxuriant fur coats with some gray fur in the melatonin group; animals in the saline group had large areas of baldness. This study demonstrates, for the first time, the antiaging effect of NAS. This effect needs to be confirmed in animals with impaired capacity to convert NAS into melatonin.

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.