• Biomolecules & Therapeutics
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• 제4권2호
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• pp.196-201
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• 1996

The N-methyl-D-aspartate (NMDA) receptor-ion channel complex is activated by the simultaneous presence of L-glutamate and glycine, allowing the binding of MK-801 to the phencyclidine (PCP) site of the receptor. The $[^3H]$MK-801 binding assay system was established for determination of pharmacological functions of test compounds acting at the glycine site of the receptor. The binding in the presence of 0.1 $\mu$M L-glutamate was increased by an agonist (glycine) in a dose-dependent fashion, while decreased by either partial agonist (R-(+)-HA-966) or antagonist (5,7-dichlorokynurenic acid: 5,7-DCKA). To distinguish partial agonism from antagonism, various concentrations of 7-chlorokynurenic acid (7-CKA) were added in the assay to eliminate the interference of the endogenous glycine present in the membrane preparations. The bindings in the presence of L-glutamate (0.1$\muM$) and 7-CKA (1, 5, or 10$\muM$) were increased by R-(+)-HA-966. Being a weak partial agonist, the extent of potentiation was much less than that by the agonist. These binding profiles were clearly distinguishable from those by the antagonist, 5,7-DCKA, which exhibited no intrinsic activity. The binding assays established in the present study are a useful system to classify ligands acting at the glycine site of the NMDA receptor by their pharmacological functions.

• 생약학회지
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• 제32권3호통권126호
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• pp.212-218
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• 2001

The water extracts of 82 Korean medicinal herbs were prepared and were examined for the binding affinity on the glycine binding site of NMDA (N-methyl-D-aspartate) receptor prepared by the synaptic membranes from the forebrains of male Sprague-Dawley rats. Among the tested, the extracts of Dioscoreae Rhizoma, Hoveniae Semen cum Fructus, Astragali Radix, Armeniacae Semen, Huttuynia cordata Herba, Acanthopanacis Cortex, Aurantii nobilis Pericarpium, Phellinus linteus, Amomi Fructus, Artemisiae capillaris Herba, Polyporus, Agastachis Herba and of Galli Stomachichum Corium were found to exhibit significant competitions with $[^3H]-MDL$ 105,519 for the glycine specific binding site of NMDA receptor in a dose dependent manner, respectively.

• Archives of Pharmacal Research
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• 제23권1호
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• pp.31-34
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• 2000

An efficient procedure for the preparation of 7,8-dichloro-6-nitro-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione(7) as a potential lead compound for the NMDA receptor glycine binding site antagonist, starting from readily available 4,5-dichloro-2-nitroaniline(8), is described. The key step in the synthesis involves the cyclization of malonic ester amide 10 to compound 11.

• Archives of Pharmacal Research
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• 제23권2호
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• pp.112-115
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• 2000

A synthetic procedure for the preparation of indole-2,3-dione derivatives 6 as a potential NMDA receptor glycine site antagonist with improved pharmacological profile compared with 2-carboxyindole derivative 5, starting from readily available 3,5-dichloroaniline (7), is described.

• Archives of Pharmacal Research
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• 제20권4호
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• pp.351-357
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• 1997

A series of 4-substituted-kynurenic acid derivatives possessing several different substituents at C4-position which are consisted of both a flexible propyloxy chain and an adjunct several type of carbonyl groups has been synthesized and evaluated for their in vitro antagonist activity at the glycine site on the NMDA receptor. Of them, N-benzoylthiourea 15c and N-phenylthiourea 15a were found to have the best in vitro binding affinity with $IC_{50}$ of 3.95 and $6.04{\mu}M$, respectively. On the other hand, in compounds 12a-c and 13 the displacement of a thiourea group to an amide or a carbamate caused a significant decrease of the in vitro binding affinity. In the SAR study of the 4-substituted kynurenic acid derivatives, it was realized that the terminal substitution pattern on a flexible C4-propyloxy chain of kynurenic acid nucleus significantly influences on the binding affinity for glycine site; the binding affinity to the NMDA receptor might be increased by the introduction of a suitable electron rich substituent at C4 of kynurenic acid nucleus.

• 고려인삼학회:학술대회논문집
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• 고려인삼학회 2004년도 추계 학술대회 및 정기총회
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• pp.7-11
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• 2004

We previously reported that ginseng inhibited NMDA receptors in cultured hippocampal neurons. Here, we further examined the detailed mechanism of ginseng-mediated inhibition using its main active ingredient, ginsenoside Rg$_3$. Co-application of ginsenoside Rg$_3$ with increasing concentrations of NMDA did not change the EC$_{50}$ of NMDA to the receptor, suggesting ginsenoside Rg$_3$ inhibits NMDA receptors without competing with the NMDA-binding site. Ginsenoside Rg$_3$-mediated inhibition also occurred in a distinctive manner from the well-characterized NMDA receptor open channel blocker, MK-801, However, ginsenoside Rg$_3$ produced its effect in a glycine concentration-dependent manner and shifted the glycine concentration-response curve to the right without changing the maximal response, suggesting the role of ginsenoside Rg$_3$ as a competitive NMDA receptor antagonist. We also demonstrated that ginsenoside Rg$_3$ significantly protected neurons against NMDA insults. Therefore, these results suggest that ginsenoside Rg$_3$ protects NMDA-induced neuronal death via a competitive interaction with the glycine-binding site of NMDA receptors in cultured hippocampal neurons.

• 한국자기학회지
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• 제16권1호
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• pp.79-83
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• 2006

광전자 회절을 이용한 정량적 구조 결정이 Cu(100)/glycine $(NH_2CH_3COOH)$ 흡착 계에 대하여 얻어졌다. $Cu(100)(2\times4)$pg-glycine $(NH_2CH_3COOH)$에서 분자는 아미노기의 질소원자, 카복실기의 두 개의 산소원자가 기판원자와 결합에 참여하고 있음이 얻어졌다. 질소원자, 산소원자 모두 atop site에 흡착을 한다. 질소원자와 산소원자 모두 atop 정 위치에서 각각 $5^{\circ}\pm4^{\circ},\;9^{\circ}\pm2^{\circ}$ 벗어난 위치에 있는 사실을 얻었다. 화학결합 길이는 Cu-N와 Cu-O모두 $2.05\pm0.02\;{\AA}$ 결정되었다. 두 개의 산소가 화학결합에 개입된 것으로 보이며, 이 결과는 Cu(110)에서 얻은 결과와 유사하다. Cu(110)$(2\times3)$ pg-glycine에서 얻은 결과를 재해석한 결과 두 산소는 동등하지 않고 한 산소원자는 다른 산소원자 보다 $0.29\;{\AA}$ 결합 높이가 차이가 있음을 보였다.

• Bulletin of the Korean Chemical Society
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• 제16권5호
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• pp.410-416
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• 1995

The proton transfer energies of gas phase glycine and alanine and those of hydrated glycine and alanine were calculated both with Hartree-Fock and $M{\Phi}ller-Plesset$ ab initio molecular orbital (MO) calculations with 6-31G** basis set. The transition states of the proton transfer of gas phase glycine was also investigated. For zwitterions, both for glycine and alanine, the water bound to -NH3+ site stabilize the complex more compared with the water bound to -CO2-. The proton transfer energy, ΔEpt, of glycine, alanine, mono-hydrated glycine, mono-hydrated alanine, di-hydrated glycine and di-hydrated alanine were obtained as 30.78 (MP2: 22.57), 31.43, 23.99 (MP2: 17.00), 24.98, 22.87, and 25.63 kcal/mol, respectively. The activation energy for proton transfer from neutral (Nt) glycine to zwitterion (Zw) glycine, Ea, was obtained as 16.13 kcal/mol and that for reverse process, Ear, was obtained as 0.85 kcal/mol. Since the transition state of the proton transfer of gas phase glycine locate near the glycine zwitterion on the potential energy surface and the shape of the potential well of the zwitterion is shallow, the zwitterion easily changed to neutral glycine through the proton transfer.

• Archives of Pharmacal Research
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• 제24권4호
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• pp.270-275
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• 2001

Bioisostere approach has been shown to be useful to augment potency or to modify certain physiological properties of a lead compound. Based upon well documented bioisosterism, an isosteric replacement of benzene ring of 4-hydroxy-2-quinolone compound (L-695902) with a thiophene moiety was carried out to prepare the title compounds, 4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b] pyrimidines 15. The resulting bioisosteric compounds 15 were evaluated for their antagonistic activity (birding assay) for NMDA receptor glycine site.

• Bulletin of the Korean Chemical Society
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• 제18권9호
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• pp.939-945
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• 1997

Several types of 4-substituted-quinoline-2-carboxylic acid derivatives possessing different substituents at C4-position such as sulfonyl, phosphonyl, carbonyl groups, or a flexible alkyl chain have been synthesized and evaluated for their in vitro antagonistic activity at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Of them, 5,7-dichloro-4-(tolylsulfonylamino)-quinoline-2-carboxylic acid 9 was found to have the best in vitro binding affinity with IC50 of 0.57 μM. On the other hand, in compounds 21 and 22 the introduction of flexible alkyl chains on C4 of the quinoline mother nuclei caused a significant decrease of the in vitro binding affinity. In addition, replacement of polar carboxylic acid group on C2 by neutral bioisosteres in compounds 23a-d also seems to be disadvantageous to in vitro activity. In the structure-activity relationship (SAR) study of the 4-substituted quinoline-2-carboxylic acid acid derivatives, it was realized that the substitution pattern on C4 significantly influences on the binding affinity for the glycine site of NMDA receptor and the binding affinity might be increased by the introduction of a suitable electron rich substituent at C4 which has the ability of H-bonding donor.