New hybrid structures based on memantine and edaravone molecules, in which the pyrazolone ring and adamantane fragments are linked by an alkyl linker, were synthesized. It was found that, in addition to the ability to block the intrachannel site of NMDA receptors, the new hybrid compounds exhibit the property of blockers of the allosteric site of NMDA receptors, which is not inherent in memantine and edaravone preparations. The most active hit compound was determined, which, along with the properties of a two-site blocker of the NMDA receptor, exhibits a pronounced activity as an inhibitor of lipid peroxidation, similarly to the drug edaravone.
Adamantane , Memantine , Memantine/pharmacology , Memantine/chemistry , Edaravone , Receptors, N-Methyl-D-Aspartate , Adamantane/pharmacology
Using the patch-clamp method in the whole cell configuration, it was shown that new conjugates of 2-aminothiophene-3-carboxylic acid with adamantane derivatives exhibit the ability to modulate CaCC activity in the single Purkinje neurons of rat cerebellum. It was noted that, depending on the nature of the substitution in the thiophene fragment, the nature of the effect on CaCC varies from inhibition to potentiation of CaCC currents. The described compounds are also blockers of the NMDA receptor ifenprodile site, which may have an additional neuroprotective contribution to the spectrum of biological activity of these compounds.
Adamantane/pharmacology , Chloride Channels/antagonists & inhibitors , Membrane Potentials/drug effects , Neurons/drug effects , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Thiophenes/pharmacology , Animals , Cells, Cultured , Male , Neurons/metabolism , Neurons/physiology , Patch-Clamp Techniques/methods , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/metabolism
Psychotropic properties of CA-7043× and CA-7050×, new fluorinated derivatives of tetrahydrocarbasoles, were examined on outbred CD1 mice and transgenic 5×FAD mice with Alzheimer disease. Both agents exerted cognitive-stimulating and anxiolytic effects in a dose of 5 mg/kg. In the new cage test, they retarded extinction of orientation and exploratory behavior. CA-7043× produced an anxiolytic effect on CD1 mice assessed in the open-field test and exerted cognitive-stimulating action in the new location test. In the same tests, CA-7050× demonstrated the cognitive-stimulating and anxiolytic effects on transgenic 5×FAD mice.
Anti-Anxiety Agents/pharmacology , Anxiety/drug therapy , Behavior, Animal/drug effects , Carbazoles/pharmacology , Exploratory Behavior/drug effects , Hydrocarbons, Fluorinated/pharmacology , Maze Learning/drug effects , Psychotropic Drugs/pharmacology , Alzheimer Disease/drug therapy , Animals , Disease Models, Animal , Male , Mice , Mice, Transgenic
Cholinesterase Inhibitors/chemistry , Esterases/antagonists & inhibitors , Esterases/ultrastructure , Fluorine Compounds/chemistry , Models, Chemical , Models, Molecular , Organophosphonates/chemistry , Binding Sites , Computer Simulation , Enzyme Activation , Esterases/chemistry , Kinetics , Protein Binding , Protein Conformation , Substrate Specificity
Esterases/antagonists & inhibitors , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Structure-Activity Relationship , Animals , Cholinesterase Inhibitors/adverse effects , Cholinesterase Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Hydrophobic and Hydrophilic Interactions , Lactates/chemistry , Organophosphorus Compounds/adverse effects , Phosphorylation
Cholinesterases/metabolism , Esterases/antagonists & inhibitors , Esterases/chemistry , Organophosphorus Compounds/metabolism , Butyrylcholinesterase/metabolism , Carboxylic Ester Hydrolases/antagonists & inhibitors , Carboxylic Ester Hydrolases/metabolism , Cholinesterase Inhibitors/pharmacology , Cholinesterases/chemistry , Esterases/metabolism , Kinetics , Phosphorylation , Phosphotransferases/metabolism
Enzyme Inhibitors/pharmacology , Fluorine/pharmacology , Organophosphonates/pharmacology , Serine Endopeptidases/metabolism , Biochemistry/methods , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Fluorine/chemistry , Humans , Magnetic Resonance Spectroscopy , Models, Chemical , Models, Theoretical , Serine Endopeptidases/chemistry , Time Factors
