DESIGN OF COMPOUNDS WITH ANTICONVULSANT ACTIVITY AMONG NMDA-RECEPTOR LIGANDS

Abstract

NMDA receptors play an important role in the development of immune responses. Therefore, the design of NMDAergic compounds presents great interest in various areas, including immunology. We have previously shown that some imidazole-4,5-dicarboxylic acid (IDA) derivatives are ligands of these receptors, and can exhibit both agonistic and antagonistic activities. In continuation of these studies and in attempt to establish the main structural parameters that determine the type of the activity, we developed a general method for synthesis of 1-, 2-mono and 1,2-disubstituted IDA derivatives. To establish the structure-activity relationship in the series under investigation, which include about 30 compounds, we try to find correlations of biological activity with the structure of compounds and some their physicochemical parameters (for example, partition coefficients between the lipophilic and hydrophilic phases). Pharmacological analysis in vivo of this set in various models under ip administration showed that a part of them induces a pre-convulsive state in mice of the CBA line, while the other part has a pronounced anticonvulsant effect on the NMDA-induced seizures. Thus, in the series of compounds under investigation substances that are both convulsants and anticonvulsants were found. The results of this study will allow us to design new drugs with anticonvulsant action.

Keywords

NMDA receptors / structure-activity relationships / seizures / antiseizure activity

RIGHTS & PERMISSIONS

Brusina M.A., Kubarskaya L.G., Iljin V.V., Nikolaev D.N., Piotrovskiy L.B.