Disease relevance of Lopac-C-121

• METHODS: As a first step in the exploration of this approach, we examined the effect of 4-chloro-kynurenine (4-Cl-KYN), which is converted by astrocytes to the potent NMDA glycine-site antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), on the in vivo epileptiform evoked potentials in the CA1 region of rats with chronic limbic epilepsy (CLE) [1].
• We investigated the therapeutic potential of 7-Chlorokynurenic acid, a potent antagonist at the glycine-modulatory site on the NMDA receptor, in terms of both neuroprotection and behavioral outcome in rats following transient forebrain ischemia [2].
• Neither 7-chlorokynurenic acid (7-CLKYNA) nor strychnine in doses of 10, 50, or 100 nmol ICV significantly altered the clonic seizure response to PTZ [3].

Psychiatry related information on Lopac-C-121

• Ameliorative effects of histamine on 7-chlorokynurenic acid-induced spatial memory deficits in rats [4].
• Glycine at low concentrations had no effect on locomotor activity, while 7-chlorokynurenic acid increased the locomotor period and decreased the burst amplitude in a dose-dependent manner [5].

High impact information on Lopac-C-121

• Effects of (+)-HA-966 and 7-chlorokynurenic acid on the kinetics of N-methyl-D-aspartate receptor agonist responses in rat cultured cortical neurons [6].
• 4. Comparisons of concentration-response curves for glycine and 7-chloro-kynurenic acid demonstrated that Mg2+ significantly increased the affinity of the NMDA receptor for glycine [7].
• Gly increased [3H]GABA release from cerebellar synaptosomes (EC50, 110.7 microM) in a strychnine- and 7-chlorokynurenic acid-insensitive manner [8].
• All three antagonists tested, viz., 7-chlorokynurenic acid (7-Cl-KYNA), kynurenic acid (KYNA), and 1-hydroxy-3-aminopyrrolidone-2 (HA-966), inhibited the binding of [3H]glycine to the NMDA receptor in a dose-dependent manner [9].
• The neuroprotective action of HA-966 and 7-chlorokynurenic acid, but not that of NMDA antagonists 3-(2-carboxypiperazine-4-yl)propylphosphonate and MK-801, could be reversed by glycine [10].

Chemical compound and disease context of Lopac-C-121

• N(alpha)-methylhistamine had no effect on 7-chlorokynurenic acid-induced memory deficits, whereas 1-methylhistamine, but not 3-methylhistamine reversed 7-chlorokynurenic acid-induced working memory deficits [4].

Biological context of Lopac-C-121

• Under these conditions, 7-chlorokynurenic acid produced a concentration-dependent block of both the initial and equilibrium response to NMDA, with a 4-fold greater sensitivity for block of the steady-state current (IC50 = 2.25 microM) than for block of the peak current (IC50 = 8.96 microM) [11].
• The competitive glycine antagonist 7-chlorokynurenic acid produced a similar shift of both the peak and steady-state dose-response curves for glycine, consistent with an equilibrium dissociation constant of 280 nM for interaction of 7-chlorokynurenic acid with the glycine binding site on NMDA receptors [11].
• In contrast, infusion of either 7-chlorokynurenic acid (400 microM) or of the N-methyl-D-aspartate receptor antagonist, D-2-amino-5-phosphonovaleric acid (100 microM), significantly attenuated or completely blocked the development of long-term potentiation [12].
• The drugs SC-49648 and 7-chlorokynurenic acid (i.p.) did not affect cGMP responses, suggesting poor bioavailability in brain [13].
• The administration of an antagonist of this receptor, 7-chloro-kynurenic acid (7-Cl KY) alone had no appreciable effect on low-frequency synaptic transmission while HFS failed to induce LTP [14].

Anatomical context of Lopac-C-121

• Both the [3H]NE releases induced from rat hippocampus synaptosomes by NMDA (no Mg++ added) and by NMDA+quisqualic acid (QA), in the presence of 1.2 mM Mg++, were prevented by 7-chloro-kynurenic acid with almost identical potency (IC50 values: 0.19 and 0.39 microM, respectively) [15].
• D-serine (glycine(B) agonist) did not reverse the PbTx-induced depression of reflexes although it reversed the 7-chlorokynurenic acid-induced depression of PSR.The results indicate that the PbTx depressed the spinal reflexes without altering the magnitude of dorsal root or ventral root activity [16].
• D(-)-2-amino-5-phosphonovaleric acid (AP5, 10(-5) to 10(-3) M) and 7-chloro-kynurenic acid (7ClKyn, 10(-6) to 10(-3) M) inhibited the basal activity of the vestibular nerve fibers [17].
• We have synthesized D-glucose or D-galactose esters of 7-chlorokynurenic acid (7ClKynA) as prodrugs to facilitate the transport of 7ClKynA across the blood-brain barrier [18].
• Antiepileptogenic action of 7-chlorokynurenic acid on amygdala kindling of rats [19].

Associations of Lopac-C-121 with other chemical compounds

• Chronic morphine treatment also altered the affinity of two noncompetitive NMDA receptor antagonists, 7-chloro-kynurenic acid and ifenprodil [20].
• In this study, we have tested the effect of the most potent and selective of these compounds, 7-chlorokynurenic acid (Cl-Kyn), on the induction of long-term potentiation, an event known to involve activation of NMDA receptors [21].
• A 5 min administration of cycloleucine (20-100 microM) or 7-chlorokynurenic acid (1-5 microM) during the delivery of high-frequency stimulation blocked the induction of LTP without affecting baseline synaptic transmission [22].
• The response to Gly-Gln was unaffected by D-amino-2-phospho-5-valeric acid (AP5) and 7-chlorokynurenic acid (7-ClKY), antagonists respectively at the ligand and allosteric glycine binding sites of the NMDA glutamate receptor subtype [23].
• WAY 100635, a 5-HT1A receptor antagonist, prevents the impairment of spatial learning caused by intrahippocampal administration of scopolamine or 7-chloro-kynurenic acid [24].

Gene context of Lopac-C-121

• Specifically, our results reveal that the frequency of miniature excitatory postsynaptic currents is significantly reduced by 7-chloro-kynurenic acid (7-Cl KYNA), a NMDA-R glycine binding site antagonist, and glycine or d-serine reverses this effect [25].

Analytical, diagnostic and therapeutic context of Lopac-C-121

• Rat behaviors in the elevated T-maze (ETM) were evaluated following tectum microinjections of either glycine (GLY, 1, 10, 80 and 120 nmol) or d-serine (D-SER, 160 and 320 nmol), the putative endogenous agonists of GLY-B site at NMDA receptor, or the respective antagonist 7-chloro-kynurenic acid (7CK, 8 nmol) [26].
• Further perfusion together to high (+ 2 mM) calcium with 0.5 mM penicillin or with 50 microM CGS 19755, but not with 50 microM 7-chlorokynurenic acid significantly decreases the degree of paired-pulse inhibition as revealed by a significative increase in the R2/R1 ratio [27].

References