ИСТИНА

The concept of «dual action» is the basic one for molecular modeling and subsequent synthesis and biological testing. We successfully used this idea for the design of new neuroprotective compounds and cognitive enhancers. First of all we have constructed the molecular models of all domains in closed and open forms of metabotropic (mGluR1-8) and ionotropic (NMDA, AMPA) glutamate receptors. The combined application of molecular modeling techniques, QSAR and artificial neural networks enabled the evaluation of ligand structural features important for high affinity to the receptors. Search for active compounds has been achieved using the idea of a specific blockade of calcium ion influx via activated NMDA receptor and a simultaneous slight potentiation of AMPA receptors. Tests of obtained hit compounds in animal model of AD-type dementia simulated by cholinotoxin AF64A, revealed a significant improvement of memory in Morris water maze test while psychotomimetic side effects were absent. On the basis of a 3D structure of the positive modulator binding site of AMPA receptor, a series of bivalent compounds based on new scaffolds has been designed using molecular docking techniques and the manual refinement of structures. Extraordinary high potency of the designed compounds starting from picomolar concentrations has been revealed, which corresponds to the highest values among all currently known positive AMPA receptor modulators. The pronounced cognitive enhancing properties have been demonstrated in a series of animal tests, while any noticeable toxicity was not evaluated for lead compounds during the preclinical studies. Secondly, we synthesized a hybrid molecule with colchicine linked to an adamantane based taxotere mimetic. These structures manifested a high cytotoxicity in vitro against A549 human lung carcinoma cells and dual mechanism of action. Optimisation have led to a such structures as N-(7-adamant-2-yloxy-7-oxoheptanoyl)-N-deacetylcolchicine [EC50(A549)6 nM], which was named tubuloclustin for its ability not only to cause disassembly of microtubules, but to promote the formation of stable tubulin clusters, morphologically distinct from microtubule bundles induced by taxol and tubulin paracrystals induced by vinblastine.