L-701,324

L-701324 is an orally active and long acting anticonvulsant with high affinity and selectivity for the glycine site on the NMDA receptor. Target: NMDA Receptor L-701324 is a potent, active anticonvulsant with a reduced propensity to activate mesolimbic dopaminergic systems in rodents. L-701324 exhibits a beneficial action in the animal model of parkinsonian rigidity, but not that of parkinsonian akinesia. L-701324 (2.5-40 mg/kg, i.p.) dose-dependently decreased the muscle tone enhanced by haloperidol (1-5 mg/kg, i.p.).

References:
[1]. Piotr Wlaz, et al. Differential effects of glycine on the anticonvulsant activity of D-cycloserine and L-701,324 in mice. Pharmacological Reports 2011,63,1231-1234

Differential effects of glycine on the anticonvulsant activity of D-cycloserine and L-701,324 in mice.[Pubmed:22180366]

Pharmacol Rep. 2011;63(5):1231-4.

The anticonvulsant effects of D-cycloserine, which is a partial agonist of the glycine/N-methyl-D-aspartate (NMDA) receptor, and L-701,324, which is a selective and potent antagonist that acts at the glycine site, were studied in electroshock-induced seizures in mice. Glycine, which is a natural full agonist that acts at the glycine site, enhanced the seizure threshold-increasing effect of D-cycloserine. L-701,324 produced a marked increase in the seizure threshold, which was significantly reversed by the administration of glycine. These results suggest that indirect glycine/NMDA antagonistic mechanisms may be responsible for the anticonvulsant action of D-cycloserine.

L-701,324, a selective antagonist at the glycine site of the NMDA receptor, counteracts haloperidol-induced muscle rigidity in rats.[Pubmed:10353425]

Psychopharmacology (Berl). 1999 Apr;143(3):235-43.

RATIONALE: It has recently been suggested that the overactivity of glutamatergic neurotransmission may contribute to the pathophysiology of Parkinson's disease. Therefore, a search for new compounds which block glutamatergic receptors and show antiparkinsonian properties in animal models of this disease seems to be justified. OBJECTIVE: The aim of this study was to determine whether L-701,324 [7-chloro-4-hydroxy-3(3-phenoxy) phenylquinoline-2-(H)-one], a selective and full antagonist at the glycine site of the NMDA receptor, counteracts parkinsonian-like muscle rigidity and catalepsy induced by haloperidol in rats. METHODS: The muscle tone was measured as the resistance developed to passive flexion and extension of the hind limb. Electromyographic (EMG) activity was additionally recorded in the gastrocnemius and tibialis anterior muscles. RESULTS: L-701,324 (2.5-40 mg/kg IP) dose-dependently decreased the muscle tone enhanced by haloperidol (1-5 mg/kg IP). Likewise, the haloperidol-enhanced resting EMG activity and the EMG reflex response to passive movements were diminished by lower and almost abolished by higher doses of L-701,324. However, up to a dose of 20 mg/kg IP, L-701,324 did not influence haloperidol (0.5 mg/kg IP)-induced catalepsy. Moreover, L-701,324 (1.25-5 mg/kg IP) given alone or together with haloperidol (0.5-1 mg/kg IP) disturbed rotarod performance. Gross observation of behaviour indicated that rats injected with L-701,324 in doses equal to or higher than 5 mg/kg, alone or in combination with haloperidol, were markedly ataxic, i.e. rats showed signs of disturbed balance and loss of control over their hind limbs. CONCLUSIONS: The present study suggests that L-701,324 exhibits a beneficial action in the animal model of parkinsonian rigidity, but not that of parkinsonian akinesia. Nonetheless, this compound is not devoid of motor side-effects.

Effects of the NMDA/glycine receptor antagonist, L-701,324, on morphine- and cocaine-induced place preference.[Pubmed:10540964]

Pol J Pharmacol. 1999 Jul-Aug;51(4):323-30.

Effects of the novel NMDA/glycine receptor antagonist, L-701,324, on morphine- and cocaine-induced conditioned place preference (CPP) were examined in male Wistar rats. After determination of initial preference, animals were conditioned with morphine (5 mg/kg, i.p.) or cocaine (5 mg/kg, i.p.) for 3 conditioning trials, alone or in combination of these drugs with L-701,324 (2.5 mg/kg and 5 mg/kg, p.o.). L-701,324 prevented acquisition of the place preference produced by morphine and cocaine. Administration of L-701,324 on the test day attenuated the expression of morphine-induced CPP, whereas it had no effect on cocaine CPP. When L-701,324 was given alone it did not affect dependent variables (i.e. time spent in non-preferred compartment) suggesting that L-701,324 did not display any reinforcing properties by itself. Our current data suggest that glycine site on the NMDA receptor complex may be involved in the mediation of the rewarding effects of drugs of abuse.

Pre-treatment with the NMDA receptor glycine-binding site antagonist L-701,324 improves pharmacosensitivity in a mouse kindling model.[Pubmed:24656981]

Epilepsy Res. 2014 May;108(4):634-43.

The glycine co-agonist binding site of the N-methyl-D-aspartat (NMDA) receptor is discussed as an interesting target for different central nervous system diseases. Antagonism at this co-agonist site has been suggested as an alternative to the use of non-competitive or competitive NMDA receptor antagonists, which are associated with a pronounced adverse effect profile in chronic epilepsy models and epilepsy patients. In the present study, we addressed the hypothesis that sub-chronic administration of the glycine-binding site antagonist L-701,324 might exert disease-modifying effects in fully kindled mice during a period with frequent seizure elicitation (massive kindling). Moreover, we analyzed whether L-701,324 exposure during this phase affects the subsequent response to an antiepileptic drug. L-701,324 treatment during the massive kindling phase did not affect ictogenesis. Mean seizure severity and cumulative seizure duration proved to be comparable between vehicle- and L-701,324-treated mice. Following withdrawal of L-701,324 seizure thresholds did not differ in a significant manner from those in animals that received vehicle injections. A low dosage of phenobarbital caused a significant increase of the generalized seizure threshold in the L-701,324 pre-treated group, whereas it did not exert a comparable effect in animals that received vehicle during the massive kindling phase. Analysis of P-glycoprotein in the hilus of the hippocampus revealed lower expression rates in L-701,324 pre-treated kindled mice. In conclusion, the data indicate that targeting of the NMDA receptor glycine-binding site does not result in anticonvulsant or disease-modifying effects. However, it might improve antiepileptic drug responses. The findings might be linked to an impact on P-glycoprotein expression. However, future studies are necessary to further evaluate the mechanisms and assess the potential of respective add-on approaches.

The atypical neuroleptic profile of the glycine/N-methyl-D-aspartate receptor antagonist, L-701,324, in rodents.[Pubmed:8627534]

J Pharmacol Exp Ther. 1996 May;277(2):578-85.

The present study has examined the glycine/N-methyl-D-aspartate antagonist, L-701-324 [7-chloro-4-hydroxy-3-(3-phenoxy)-phenyl-2 (H)quinolone] in rodent behavioral tests commonly used to predict antipsychotic potential and side effect liability in humans. Pretreatment with L-701,324 dose-dependently antagonized amphetamine-induced hyperactivity in the mouse (ED50 = 1.12 +/- 0.45 mg/kg p.o.), an effect which was similar to that of the classical neuroleptic, haloperidol, and the atypical neuroleptic, clozapine. In addition, p.o. administration of L-701,324 (2.5 or 5 mg/kg) attenuated the hyperactivity response induced by amphetamine infusion into the rat nucleus accumbens. In contrast to haloperidol, however, stereotyped sniffing and licking/biting, induced by either the systemic administration of apomorphine or infusion of amphetamine into the striatum, was not altered in rats pretreated with L-701,324 (30 or 100 mg/kg p.o.). Furthermore, L-701,324 failed to impair spontaneous locomotor activity or induce catalepsy in the mouse at doses > or = 100 mg/kg. Although a significant reduction in spontaneous activity was observed in rats pretreated with L-701,324, the minimum effective dose (10 mg/kg p.o.) was 2-fold greater than that which abolished amphetamine-induced hyperactivity in this species. Thus, L-701,324 selectively blocks behaviors associated with the activation of the mesolimbic dopamine system suggesting that glycine/N-methyl-D-aspartate receptor antagonists may offer a novel approach to the treatment of schizophrenia in humans.

Anticonvulsant and behavioral profile of L-701,324, a potent, orally active antagonist at the glycine modulatory site on the N-methyl-D-aspartate receptor complex.[Pubmed:8930150]

J Pharmacol Exp Ther. 1996 Nov;279(2):492-501.

The anticonvulsant and behavioral profile of the glycine/N-methyl-D-aspartate receptor antagonist L-701,324 [7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(H)quinolone] has been examined in rodents. In mice, L-701,324 protected against seizures induced by N-methyl-DL-aspartate (ED50 = 3,4 mg/kg i.v.), pentylenetetrazol (ED50 = 2.8 mg/kg i.v.) and electroshock (ED50 = 1.4 mg/kg i.v.) but was most potent against audiogenic seizures in DBA/2 mice (ED50 = 0.96 mg/kg i.p.). L-701,324 was also active p.o. in mice (ED50 = 1.9,6.7, 20.7 and 34 mg/kg against audiogenic, electroshock-induced, N-methyl-DL-aspartate-induced and pentylenetetrazol-induced seizures, respectively) but showed weaker anticonvulsant activity in rats (ED50 = 90.5 mg/kg p.o., compared with 2.3 mg/kg i.v., against pentylenetetrazol-induced seizures), most probably because of the lower brain concentrations achieved in this species. Although anticonvulsant activity was also associated with impaired rotarod performance, L-701,324 failed to significantly increase locomotor activity or dopamine turnover in the nucleus accumbens at doses of up to 10 mg/kg i.v. in mice. Thus, in contrast to N-methyl-D-aspartate receptor ion channel blockers such as MK-801 (dizocilpine), L-701,324 is a potent, p.o. active anticonvulsant with a reduced propensity to activate mesolimbic dopaminergic systems in rodents.

Inhibition of cortical spreading depression by L-701,324, a novel antagonist at the glycine site of the N-methyl-D-aspartate receptor complex.[Pubmed:8851513]

Br J Pharmacol. 1996 Mar;117(5):931-7.

1. Spreading depression (SD) is a propagating transient suppression of electrical activity, associated with cellular depolarization, which probably underlies the migraine aura and may contribute to neuronal damage in focal ischaemia. The purpose of this study was to examine whether L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2-(1H)-quinolone), a high affinity antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex, inhibits the initiation and propagation of K(+)-induced SD in the rat cerebral cortex in vivo. 2. Microdialysis probes incorporating a recording electrode were implanted in the cerebral cortex of anaesthetized rats and perfused with artificial cerebrospinal fluid (ACSF). Five episodes of repetitive SD were elicited by switching to a medium containing 130 mM K+ for 20 min, each separated by 40 min of recovery (i.e. perfusion with normal ACSF). The brief negative shifts of the extracellular direct current (d.c.) potential, characteristic of SD elicitation, were recorded with the microdialysis electrode and a reference electrode placed under the scalp. Propagation of SD was examined using glass capillary electrodes inserted about 3 mm posterior to the microdialysis electrode. L-701,324 (5 or 10 mg kg-1) or its vehicle were administered i.v. 10 min after the end of the second K(+)-stimulus. The effects of L-701,324 were compared to those of dizocilpine (MK-801; 1 mg kg-1 i.v.), a NMDA-channel blocker known to potently block SD elicitation. 3. Potassium-induced SD initiation was inhibited by 10 mg kg-1 (but not by 5 mg kg-1) of L-701,324. Thirty minutes after administration of 10 mg kg-1 L-701,324, the cumulative area of SD peaks elicited during 20 min was 15.3 +/- 2.1 mV min, versus 23.2 +/- 1.1 mV min in animals which received only the drug vehicle (P < 0.02; n = 6). The delay between application of 130 mM K+ and occurrence of the first SD was also significantly increased. It was approximately doubled in animals treated with 10 mg kg-1 of L-701,324. 4. SD propagation was more sensitive than SD elicitation to L-701,324, as both 5 and 10 mg kg-1 produced an effective inhibition. Even at the lower dose of 5 mg kg-1, L-701,324 completely blocked the propagation of SD elicited 30 min after drug administration. This differential sensitivity of SD elicitation and propagation is not specific to L-701,324 since it was previously observed with other drugs. At doses effective against SD, L-701,324 did not produce any marked alterations of the electroencephalogram. 5. L-701,324 (10 mg kg-1) and MK-801 (1 mg kg-1) had identical effects on the d.c. potential when administered during the recovery which followed the second K+ stimulus. Both drugs produced a positive shift of around 4.5 mV within 10 min of i.v. drug administration, indicating rapid drug penetration into the CNS. Paradoxically, L-701,324 (10 mg kg-1) was markedly less effective than MK-801 (1 mg kg-1) in blocking SD, since this dose of MK-801 was sufficient virtually to abolish SD initiation and completely block its propagation. The higher potency of MK-801 against SD may reflect its use-dependency, i.e. binding of MK-801 and channel blockade are enhanced when the NMDA-receptor ionophore is open. 6. Taken together, these data demonstrate that L-701,324 has an inhibitory effect on both SD initiation and propagation. This action may be beneficial in focal ischaemia, and possibly also against migraine, especially as this drug was shown to be active when administered orally.

L-701324 is an orally active and long acting anticonvulsant with high affinity and selectivity for the glycine site on the NMDA receptor.

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