Recently, the phenomenon of favorable interaction between heavy halogen atom (Cl, Br, I) and Lewis bases was rediscovered. It is called halogen bonding (XB) and attracts much attention [1,2] for several reasons. First, it is found in many different systems such as organic crystals, liquid crystals, polymers, biological macromolecules and their complexes. Second, the interaction energy is comparable to traditional hydrogen bonding energies. Third, it is able to form directional interactions in hydrophobic environment and complement [2] identified previously and widely used interaction patterns, such as hydrogen bonding, electrostatic interactions, dispersion interactions, hydrophobic interactions, aromatic stacking. At last, XB contradicts traditional conception of halogen in molecule being only a Lewis base. Although the nature of XB is still under investigation, the main hypothesis states that electrostatic interaction is the main factor determining its energetics [3]. Despite several models for empirical description of XB were reported earlier, none became a scheme of common choice, due to lack of systematic investigation comparing different approaches. Moreover, development of fast empirical models capable of reliable description of XB is of crucial significance to progress in its better understanding and its successful application.

The comparative study of cognition–enhancing properties of anti–cholinergic agent Aricept, antagonist of NMDA receptor Memantine and newly developed agent Dimebon with multifaceted mechanism of action [US Patent 6,187,785; Bachurin et al. Ann.N.Y.Acad. Sci., 2001, 939:425] was made. Study of compounds effects on spatial learning and memory was performed on rats treated (i.c.v.) with cholinotoxin AF64A in Morris water maze test. Aricept and Memantine have been tested in dose of 2 mg/kg per os, Dimebon was tested in dose 0.05 mg/kg per os, according to the preliminary results. Despite rather large escape latency observed on the 5th day of the training, Aricept significantly decreased its value and improved trajectory at the search of the platform in comparison with AF64A–treated rats. Memantine and Dimebon demonstrated strong tendency to decrease the escape latency. On the 11th day of the training the AF64A–treated rats received all compouds escaped on the platform for almost the same time significantly different from AF64A group. The best values of the track's directionality (straightness index) on the 15th day were obtained for all tested compounds. However, 11 days break (up to 26th day) in the training procedure after finishing the compounds injections led to a considerable deterioration of the spatial orientation of the rats received Aricept and its slight decrease for other groups, in contrast to Memantine–, and especially Dimebon–treated rats for which the ability to find the platform remained almost the same as on the 15 day. Statistically significant differences for all groups relative AF64A–injected rats were obtained by the straightness index and cumulative distance to platform. Rats that received Aricept demonstrated the most significant improvements of the cognitive functions. However, a significant imperfection of Aricept is its symptomatic effect, namely, cancellation of its injections leads to the decrease of the cognitive functions of rats down to the level of ‘toxin–treated’ group. Memantine and Dimebon demonstrated more prolonged effect observed after finishing of injections that let us suppose their influence on regenerative and/or compensatory processes in brain.

Abstract: 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.

A bstract : 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 β‐amyloid fragment (Aβ25−35, EC 50 = 25 μM). In vitro , Dimebon displayed Ca 2+ ‐blocking properties (IC 50 = 57 μM, on isolated rat ileum intestine) and pronounced anticholinesterase activity (IC 50 = 7.9 μM and 42 μM for butyrylcholine esterase and acetylcholine esterase, respectively). It also exhibited strong anti‐NMDA activity in the prevention of NMDA‐induced seizures in mice (EC 50 = 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.