DESIGN OF COMPOUNDS WITH ANTICONVULSANT ACTIVITY AMONG NMDA-RECEPTOR LIGANDS

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.

Ionotropic Glutamate Receptors in Cerebral Microvascular Endothelium are Functionally Linked to Heme Oxygenase

Vasodilator effects of glutamate in the cerebral circulation are, in part, mediated by carbon monoxide (CO), which is formed from heme via the heme oxygenase (HO) pathway. The hypothesis addressed was that glutamate receptors (GluRs) in cerebral microvascular endothelium are functionally linked to HO. Using a radioligand binding and immunoblotting, GluRs were characterized in cerebral microvascular endothelial cells (CMVEC) from newborn pigs. High-affinity (80 nmol/L) reversible binding of [H]Glutamate ([3H]Glu) was detected in CMVEC membranes. The N-methyl-D-aspartate (NMDA) receptor ligands—NMDA, quinolinic acid, (±)1-aminocyclopentane- cis-1,3-dicarboxylic acid ( cis-ACPD), AP5, 4C3HPG, and CPP—and the (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptor ligands—AMPA, kainic acid, quisqualic acid, DNQX, and CNQX—displaced 20% to 30% of bound [3H]Glu in CMVEC membranes. Metabotropic GluRs antagonists (4CPG, PHCC, and CPPG) did not displace bound [3H]Glu. L-Aspartate, an agonist of GluRs and glutamate transporters, displaced 80% or more of bound [3H]Glu. Ionotropic (NR1 and GluR1) and metabotropic (mGluR1α) GluRs were detected in CMVEC by immunoblotting. Glutamate, aspartate, cis-ACPD, AMPA, ( RS)-2-amino-(3-hydroxy-5 -tert-butylisoxazol-4-yl)propanoic acid (ATPA), and kainate (10−5 mol/L) increased HO-directed CO formation by isolated cerebral microvessels and by cultured CMVEC. These data in newborn pigs suggest that CMVEC express ionotropic GluRs that are functionally linked to HO. GluR-mediated increases in CO formation by vascular endothelium may result in increase in cerebral blood flow.