A new class of agonists and antagonists of N-methyl-D-aspartic acid receptors: derivatives of imidazole-4,5- and pyrazole-3,4-dicarboxylic acids.

Studies of imidazole-4,5- and pyrazole-3,4-dicarboxylic acid derivatives revealed a number of new agonists and antagonists of N-methyl-D-aspartic acid (NMDA) receptors. Studies were based on whole-cell patch-clamp methods applied to rat hippocampus pyramidal cells. Increases in the lipophilicity of the environment of the nitrogen atom, keeping the distance between the terminal acid functions constant, led to a weakening of NMDA antagonism and increases in NMDA antagonism. Increases in the lipophilicity around the nitrogen atom could also lead to less of selectivity in the interaction with NMDA receptors and the appearance of non-NMDA antagonist properties.

[A new class of N-methyl-D-aspartic acid receptor agonists and antagonists--derivatives of imidazole-4,5- and pyrazole-3,4-dicarboxylic acids]. / Novyi klass agonistov i antagonistov retseptorov N-metil-D-asparaginovoi kisloty--proizvodnye imidazol-4,5- i pirazol-3,4-dikarbonovykh kislot.

New agonists and antagonists of the N-methyl-D-aspartic acid (NMDA) receptors were found among the derivatives of 1- or 2-alkyl-substituted imidazole-4,5- and pyrazole-3,4-dicarboxylic acids. Lipophilic surrounding of the nitrogen atom in these compounds was found to determine their ability to be either agonists or antagonists, while the distance between the terminal acidic functions was the same. An increase in the lipophilicity can also cause loss of selective action upon the NMDA receptors and occurrence of non- NMDA antagonistic activity.

[Effect of trans-ACPD, a specific agonist of glutamate interacting with metabotropic receptors, on synaptic transmission in the rat hippocampus]. / Vliianie trans-ASPD--spetsificheskogo agonista glutamata, vzaimodeistvuiushchego s metabotropnymi retseptorami, na sinapticheskuiu peredachu v gippokampe krys.

Trans-ACPD, a cyclic analogue of glutamate, has been studied for its influence on field potentials and excitatory postsynaptic currents (EPSCs) in the CA1 layer. Being applied in concentration 50 microM and above, trans-ACPD completely and reversibly inhibited excitatory postsynaptic field potentials but has no effect on EPSCs. Trans-ACPD in the same concentration reversibly reduced the amplitude of antidromic population spike in the CA1 layer, but has an insignificant effect on antidromic population spike in the CA3 layer.

[Analysis of synaptic transmission in rat hippocampal slices using a modified method of potential fixation]. / Issledovanie sinapticheskoi peredachi v srezakh gippokampa krys s primeneniem modifitsirovannoi metodiki fiksatsii potentsiala.

A new approach for the whole-cell recording in slices is suggested as simpler and less expensive one than those known before. Electrophysiological characteristics of excitatory postsynaptic currents are obtained. Two types of glutamate receptors are shown to be involved. The kynurenic acid is proved to exert more prominent effect on the NMDA-receptor mediated current. Biphasic action of adenosine, a wide spread neuromodulator, on synaptic transmission is shown.

[Pentobarbital interaction with the GABA-activated ion channels of the neurons in the rat cerebellum]. / Vzaimodeistvie pentobarbitala s GAMK-aktiviruemymi ionnymi kanalami neironov mozzhechka krys.

GABA and barbiturate-activated currents of isolated single neurons in the rat cerebellum were studied by means of the concentration clamp, voltage clamp and intracellular perfusion methods. The dissociation constant (Kd) was 3 +/- 0.8.10(-5) M. Pentobarbital potentiated the GABA-induced conduction of isolated neurons. The dose-effect for GABA shifted along the abscissa axes. Optimal concentrations which potentiated the GABA effect were within 10(-6)-10(-4) M. The pentobarbital concentrations above 5.10(-4) M without GABA activated the Cl conductance. The short-time conductance during fast pentobarbital washing off was found to increase.

[Argiopine, argiopinines and pseudoargiopinines--blockers of the glutamate receptors in hippocampal neurons]. / Argiopin, argiopininy i psevdoargiopininy--blokatory glutamatnykh retseptorov v neironakh gippokampa.

Several homologous low-molecular weight compounds were purified from venom of spider Argiope lobata. They selectively blocked ionic currents elicited by glutamate and its agonist kainate in the membrane of isolated hippocampal neurons of rat. Three groups of these compounds--argiopine, argiopinines and pseudoargiopinines, blocked glutamate- and kainate-activated ionic currents in a voltage-dependent manner, acting preferentially on agonist-activated ionic channels. These compounds did not change the Kd values for both agonists. The blocking action was partially reversible for argiopine and poorly reversible for other compounds. Rate constants for the interaction of toxins with membrane receptors were estimated from the dependences of two-component kinetics of the blocking action and its recovery on toxin concentrations. Argiopine, argiopinines and pseudoargiopinines may be useful tools for further electrophysiological and biochemical investigation of the mammalian CNS glutamate receptors.

[Blocking action of Nephila clavata spider toxin on ionic currents activated by glutamate and its agonists in isolated hippocampal neurons]. / Blokiruiushchee deistvie iada pauka Nephila clavata na ionnye toki, aktiviruemye glutamatom i ego agonistami v izolirovannykh neironakh gippokampa.

The blocking action of the Nephila clavata spider neurotoxin was studied using the concentration clamp method in isolated neurons of the rat hippocampus. Crude venom JSTX blocked L-glutamate-, quisqualate- and kainate-activated ionic currents mediated by activation of the non-N-methyl-D-aspartate (non-NMDA) membrane receptors. Ionic currents elicited by all agonists were depressed by crude JSTX venom to 34-35% of its initial amplitude with no recovery during prolonged washing. An active fraction of JSTX venom blocked ionic currents almost completely, but its action was partially reversible. The concentration dependences of blocking kinetics allowed determining the rate constants of JSTX interaction with glutamate receptors. It is supposed that JSTX blocks the non-NMDA ionic channels in some of their open states and may be one of useful tools in further biochemical and electrophysiological characterization of the glutamate-mediated synaptic transmission.

[Rapid pH changes associated with synaptic transmission in isolated slices of the mammalian hippocampus]. / Bystrye izmeneniia pH, sviazannye s sinapticheskoi peredachei v izolirovannykh srezakh gippokampa mlekopitaiushchikh.

To perform rapid optical detection of possible pH changes accompanying electrical activity hippocampal slices were stained with pH indicator--phenol red (0.2 mM). Electrical response of granular and pyramidal cells was evoked by stimulation of perforant path, Schaffer collateral and commissural afferents in the stratum radiatum. Biphasic pH changes occurred both in pyramidal and granular cells: rapid acid changes, with the maximum reached in several msec, were followed by alkaline changes lasting up to one sec. pH changes disappeared with the blocking of synaptic transmission by Mg2+ (10 mM) and were absent in antidromic stimulation of granular cells. pH changes are believed to be related to the processes accompanying synaptic transmission.

[ATP-activated ion conductance in the somatic membrane of the neurons of mammalian sensory ganglia]. / ATF-aktiviruemaia ionnaia provodimost' v somaticheskoi membrane neironov sensornykh gangliev mlekopitaiushchikh.

The receptors for ATP were found on the external surface of the somatic membrane of mammalian sensory neurons. Their activation was accompanied by an increase in the membrane permeability to monovalent cations. ATP-operated ionic channels were low-selective and permeable to Tris and TEA ions. Simultaneously these channels demonstrated strong anomalous rectification. While ATP and ADP are agonists for the described receptors, AMP and adenosine are their competitive blockers. ATP-activated currents demonstrate rapid activation and slow desensitisation. The time constant for the latter process is about 2s.

[Blocking of proton-activated sodium permeability of the membranes of trigeminal ganglion neurons in the rat by organic cations]. / Blokirovanie proton-aktiviruemoi natrievoi pronitsaemosti membrany neironov trigeminal'nogo gangliia krysy organicheskimi kationami.

The effect of amiloride, 2- and 4-aminopyridines, tetraethylammonium, guanidine on proton-induced membrane permeability was investigated in perfused neurons from rat trigeminal ganglia. When applied externally these substances produced a rapid and reversible blocking action on the inwardly directed proton-induced current. The degree of blocking increased with hyperpolarization and with a decrease in the intracellular concentration of permeable cations. The initially linear current-voltage relationship became nonlinear. Amyloride with effective concentrations between 10(-6)-10(-4) M was the most potent blocker among the substances tested.