Development of new potential drugs with psychotropic activity among phosphorylacetohydrazides and other phosphorylated carboxylic acids derivatives - priority area of Kazan school of psychopharmacologists

Abstract

In the present review professors A.I. Razumov and I.V. Zaikonnikova ideas development on the prospects of potential drugs investigation in the class of phosphorylated carboxylic acids are described. The first representative of these compounds, approved for clinical use, became a difenilphosphorylacetic acid hydrazide - the drug phosenazid (diphenizid, phosphabenzide, gidiphen) with a tranquilizing, anti-alcohol, antidepressant and antiepileptic properties. Continuing research, we studied the new series of phosphorylacetohydrazides and found that the 4-dimethylaminophenyl, 2’-chloroethoxyphosphorylacetic acid hydrazide (CAPAH) improves memory and learning in normal and pathological conditions, shows neuroprotective properties, corrects behavioral disorders in double-transgenic mice with the Alzheimer’s disease, has antidepressant properties. Hydrazide of 4-dimethylaminophenyl,2’-chloroethoxyphosphorylacetohydrazide acid has an original mechanism of action, which is its ability to enhance glutamatergic transmission through NMDA-receptors strychnine-insensitive glycine sites; enhances the interaction with the main mediator in the cholinergic synapses through neurokinin NK-1 receptors similar to substance P neuropeptide; has membranolipotropic effect by changing the phosphatidylcholine membrane bilayer organization, what may contribute to the positive effect on the receptors function. Using computer-aided prognosis, design and synthesis of phosphorylacetohydrazides new series and other derivatives of phosphorylated carboxylic acids was made, their nootropic, antidepressant and tranquilizing properties, some aspects of the mechanism of action were investigated, the main pharmacophores were identified and directions in the most promising compounds development were determined. The review also presents the research results analysis on the development of phosphorylacetohydrazides targeted delivery methods using calixarenes and polymer nanoparticles based on interpolyelectrolyte complexes. It is concluded that the development of new phosphorylacetohydrazides and other derivatives of phosphorylated carboxylic acids as potential drugs opens new possibilities of this unique class of compounds.