L-689,560

Kb: 130 nM

L-689,560 is a very potent antagonist at the glycine-NMDA site. The N-methyl-D-aspartate (NMDA) subtype of excitatorynamino acid receptor has been proved adequately that its relevant antagonists can reduce ischaemic brain damage (particularly in experimental models of focal cerebral ischaemia).

In vitro: L-689560 is described as one of the most potent NMDA antagonists and [4'-3H]-L-689560 has been thought to be a highly specific radioligand for the glycine site. In consistent with the 5,7-disubstituted kynurenates, the tetrahydroquinolines are selective antagonists of glycine site NMDA, L-689560 exhibiting at least 3 orders of magnitude selectivity versus the glutamate site [1].

In vivo: MDL100748 with an ED50 of 83 mg kg-1 can prevent audiogenic seizures in susceptible mice after systemic injection. As a standard L689560, its subsequent analogues have been compared; the displacement of [3H] L689560 has often been used to displace that of [3H] glycine as an alternative assay. L701252, a quinones (the retention of a keto grouping at position 3), has been against L689560 binding (IC50 of 420 nM) and against seizures (ED50 of 4.1 mg kg-1) in DBA/2 mice. A group of sulfonamide analogues of kynurenic acid are also in active among the 2-quinolone series. Those of a series of 3,4-dihydroquinolones and tetrahydroquinolines with a nitrosubstituent at 3-position were selective antagonists at the NMDA receptor glycine site if they bore a bulky grouping in the position 4. The compound with no substitution at position 4 was proved to be one of the most effective broad-spectrum antagonists against NMDA and AMPA receptors [2].

Clinical trial: So far, no clinical study has been conducted.

References:
[1].  Leeson PD, Carling RW, Moore KW, Moseley AM, Smith JD, Stevenson G, Chan T, Baker R, Foster AC, Grimwood S, et al. 4-Amido-2-carboxytetrahydroquinolines. Structure-activity relationships for antagonism at the glycine site of the NMDA receptor. J Med Chem. 1992 May 29;35 (11): 1954-68.
[2].  Stone TW. Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection. Trends Pharmacol Sci. 2000 Apr; 21(4):149-54.

Catalytic enantioselective Reissert-type reaction: development and application to the synthesis of a potent NMDA receptor antagonist (-)-L-689,560 using a solid-supported catalyst.[Pubmed:11448184]

J Am Chem Soc. 2001 Jul 18;123(28):6801-8.

Full details of the first catalytic enantioselective Reissert-type reaction are described. Utilizing the Lewis acid-Lewis base bifunctional catalyst 5 or 6 (9 mol %), the Reissert products were obtained in 57 to 99% yield with 54 to 96% ee. Electron-rich quinolines produced better yields and enantioselectivities than electron-deficient substrates. Kinetic studies indicated that the reaction should proceed via the rate-determining acyl quinolinium formation, followed by the attack of a cyanide. The catalyst does not facilitate the first rate-determining step; however, it strongly facilitates the second cyanation step. The reaction was successfully applied to an efficient catalytic asymmetric synthesis of a potent NMDA receptor antagonist (-)-L-689,560. A key step is the one-pot process using the Reissert-type reaction from quinoline 1f, followed by stereoselective reduction of the resulting enamine 2f. This step gave the key intermediate 20 in 91% yield with 93% ee, using 1 mol % of 6. The enantiomerically pure target compound was obtained through 10 operations (including recrystallization) in total yield of 47%. Furthermore, 6 was immobilized to JandaJEL, and the resulting solid-supported catalyst 11 afforded 20 in a comparable yield to the homogeneous 6, but with slightly lower enantioselectivity.

Deficit of [3H]L-689,560 binding to the glycine site of the glutamate/NMDA receptor in the brain in Huntington's disease.[Pubmed:7964888]

J Neurol Sci. 1994 Aug;125(1):46-9.

Binding of [3H]L-689,560 to the glycine site of the glutamate/NMDA receptor was carried out using post-mortem brain tissue from patients with Huntington's disease (HD) and from matched controls. Decreased binding site density (by 62% in the caudate nucleus, 20% in the frontal cortex) was identified in HD. The deficit found in the caudate nucleus in HD correlated with deficits of GABA and glutamate concentrations and thus may reflect the ongoing disease process.

Polyamines modulate [3H]L-689,560 binding to the glycine site of the NMDA receptor from rat brain.[Pubmed:8137882]

Eur J Pharmacol. 1994 Jan 1;266(1):43-50.

The N-methyl-D-aspartate (NMDA) receptor complex possesses distinct recognition sites for glutamate, glycine and polyamines, which appear to be allosterically linked. We have investigated the effects of polyamines on the binding of the glycine site antagonist [3H](+/-)-4-(trans)-2-carboxy-5,7-dichloro-4-phenylaminocarbonylamino - 1,2,3,4-tetrahydroquinoline ([3H]L-689,560), using rat cortex/hippocampus P2 membranes. Spermine and spermidine partially inhibited [3H]L-689,560 binding under non-equilibrium conditions, with IC50 values of 25.9 and 106 microM, respectively. The putative polyamine site antagonists arcaine, 1,10-diaminodecane, diethylenetriamine and putrescine had no effect on [3H]L-689,560 binding per se at 1 mM. The inhibition of [3H]L-689,560 binding by spermine was antagonised by arcaine in a competitive manner, but not by 1,10-diaminodecane, diethylenetriamine or putrescine. Kinetic analysis revealed that spermine (100 microM) decreased the association and dissociation rates of [3H]L-689,560 binding. In saturation experiments 100 microM spermine increased the KD for [3H]L-689,560 binding from 1.99 nM to 4.03 nM, with no effect on the number of binding sites. Spermine increased the affinity of glycine site agonists in displacing [3H]L-689,560 binding, with no effect on inhibition by partial agonists or antagonists, suggesting that spermine promotes an 'agonist-preferring' state. Modulation of [3H]L-689,560 binding by agonists for the polyamine and glutamate sites on the NMDA receptor did not appear to be additive in nature.

Medium supplementation with zinc enables detection of imipramine-induced adaptation in glycine/NMDA receptors labeled with [3H]L-689,560.[Pubmed:17085868]

Pharmacol Rep. 2006 Sep-Oct;58(5):753-7.

Antidepressant drugs after chronic administration induce adaptive changes in the NMDA receptor complex. Radioligand-receptorbinding studies using [3H]5,7-dichlorokynurenic acid demonstrated a "down-regulation" of the glycine site/NMDA receptor following chronic treatment with antidepressants and electroconvulsive shock. However, binding procedure using this radioligand is time consuming because it requires the use of centrifugation method in the separation process. The introduction of a new radioligand of glycine/NMDA receptor, [3H]L-689,560 enables the application of a rapid filtration method. In the present study we demonstrate that 2-week treatment with imipramine (15 mg/kg ip) did not evoke alterations in specific [3H]L-689,560 binding and in IC50 value of glycine in displacing [3H]L-689,560 binding in the mouse or rat cortex. However, longer, a 4-week treatment with imipramine induced a significant 71% increase in IC50 value in displacing [3H]L-689.560 binding in the mouse cortex. Moreover, the presence of zinc in the incubation media, dose-dependently enhances detection of imipramine-induced increase in IC50 value of glycine in displacing [3H]L-689,560 binding in the rat cortex. The present data indicate that: (1) [3H]L-689,560 may be a suitable ligand for assessing adaptation of the glycine/NMDA sites and (2) the presence of zinc enhances detection of imipramine-induced reduction of glycine affinity for glycine/NMDA receptors labeled with [3H]L-689,560 which further indicates a significance of zinc in the mechanism of antidepressant treatment.

Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection.[Pubmed:10740291]

Trends Pharmacol Sci. 2000 Apr;21(4):149-54.

Manipulation of the kynurenine pathway of tryptophan metabolism has yielded a plethora of agents that are now being developed as neuroprotectants and anticonvulsants. This pathway is involved in the production of the excitotoxin quinolinic acid and the neuroprotectant kynurenic acid. Approaches used in the development of therapeutic agents include production of analogues or pro-drugs of kynurenic acid and inhibitors of the enzyme responsible for the synthesis of quinolinic acid. Indeed, analogues of the amino acid receptor antagonist kynurenic acid are now in, or are about to enter, clinical trials for stroke and related disorders. This review summarizes the mechanism of action of these various agents, the development of glutamate receptor antagonists from kynurenic acid and the range of their potential uses in neurology and psychiatry.

4-Amido-2-carboxytetrahydroquinolines. Structure-activity relationships for antagonism at the glycine site of the NMDA receptor.[Pubmed:1534584]

J Med Chem. 1992 May 29;35(11):1954-68.

trans-2-Carboxy-5,7-dichloro-4-amidotetrahydroquinolines, evolved from the lead 5,7-dichlorokynurenic acid, have been synthesized and tested for in vitro antagonist activity at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Optimization of the 4-substituent has provided antagonists having nanomolar affinity, including the urea trans-2-carboxy-5,7-dichloro-4[[(phenylamino)carbonyl]amino]-1,2,3, 4-tetrahydroquinoline (35; IC50 = 7.4 nM vs [3H]glycine binding; Kb = 130 nM for block of NMDA responses in the rat cortical slice), which is one of the most potent NMDA antagonists yet found. The absolute stereochemical requirements for binding were found to be 2S,4R, showing that, in common with other glycine-site NMDA receptor ligands, the unnatural configuration at the alpha-amino acid center is required. The preferred conformation of the trans-2,4-disubstituted tetrahydroquinoline system, as shown by X-ray crystallography and 1H NMR studies, places the 2-carboxyl pseudoequatorial and the 4-substituent pseudoaxial. Modifications of the 4-amide show that bulky substituents are tolerated and reveal the critical importance for activity of correct positioning of the carbonyl group. The high affinity of trans-2-carboxy-5,7-dichloro-4-[1-(3-phenyl-2-oxoimidazolidinyl)]- 1,2,3,4-tetrahydroquinoline (55; IC50 = 6 nM) suggests that the Z,Z conformer of the phenyl urea moiety in 35 is recognized by the receptor. Molecular modeling studies show that the 4-carbonyl groups of the kynurenic acids, the tetrahydroquinolines, and related antagonists based on N-(chlorophenyl)glycine, can interact with a single putative H-bond donor on the receptor. The results allow the establishment of a three-dimensional pharmacophore of the glycine receptor antagonist site, incorporating a newly defined bulk tolerance/hydrophobic region.

L-689560 is a potent N-methyl-D-aspartate (NMDA) receptor antagonist at the GluN1 glycine binding site. L-689560 is widely used as a radiolabeled ligand in binding studies and used for study the roles of NMDA receptors in normal neurological processes as well as in diseases.

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