CoMFA, Synthesis, and Pharmacological Evaluation of (E)-3-(2-Carboxy-2-arylvinyl)-4,6-dichloro-1H-indole-2-carboxylic Acids:  3-[2-(3-Aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic Acid, a Potent Selective Glycine-Site NMDA Receptor Antagonist

Baron, Bruce M.; Cregge, Robert J.; Farr, Robert A.; Friedrich, Dirk; Gross, Raymond S.; Harrison, Boyd L.; Janowick, David A.; Matthews, Donald P.; McCloskey, Timothy C.; Meikrantz, Scott; Nyce, P. L.; Vaz, Roy J.; Metz, William A.

doi:10.1021/jm0491849

Cited by 29 publications

(13 citation statements)

References 40 publications

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“…We came across some studies involving 3D-CoMFA (Comparative Molecular Field analysis) methodology [32,33,34,35,36]. Although quite routinely reported; observations from such studies are difficult to compare with already established QSAR studies.…”

Section: Resultsmentioning

confidence: 99%

Dual Allosteric Effect in Glycine/NMDA Receptor Antagonism: A Comparative QSAR Approach

Sharma

Gupta

2010

Pharmaceuticals

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A comparative Hansch type QSAR study was conducted using multiple regression analysis on various sets of quinoxalines, quinoxalin-4-ones, quinazoline-2-carboxylates, 4-hydroxyquinolin-2(1H)-ones, 2-carboxytetrahydroquinolines, phenyl-hydroxy-quinolones, nitroquinolones and 4-substituted-3-phenylquinolin-2(1H)-ones as selective glycine/NMDA site antagonists. Ten statistically validated equations were developed, which indicated the importance of CMR, Verloop’s sterimol L1 and ClogP parameters in contributing towards biological activity. Interestingly, normal and inverse parabolic relationships were found with CMR in different series, indicating a dual allosteric binding mode in glycine/NMDA antagonism. Equations reveal an optimum CMR of 10 ± 10% is required for good potency of antagonists. Other equations indicate the presence of anionic functionality at 4-position of quinoline/quinolone ring system is not absolutely required for effective binding. The observations are laterally validated and in accordance with previous studies.

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Section: Resultsmentioning

confidence: 99%

Dual Allosteric Effect in Glycine/NMDA Receptor Antagonism: A Comparative QSAR Approach

Sharma

Gupta

2010

Pharmaceuticals

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“…Such information will be helpful in identifying new classes of glycine antagonists such as subtype selective antagonists. Still challenges for the development of NMDA-glycine antagonists are present [85][86][87][88][89][90].…”

Section: Resultsmentioning

confidence: 99%

Tricyclic Quinoxalinediones, Aza-kynurenic Acids, and Indole-2- Carboxylic Acids as In Vivo Active NMDA-Glycine Antagonists

Nagata¹,

Katayama²,

Ohtani³

et al. 2006

CTMC

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This review article describes the development of in vivo active antagonists for the glycine binding site of the N-Methyl-D-Aspartate (NMDA) receptor. There were several difficulties in identifying a class of antagonists with in vivo efficacy and only a few compounds succeeded in emerging with activity in vivo. A series of tricyclic quinoxalinediones was highly potent glycine antagonists in vitro and the derivatives having a zwitterionic moiety including SM-18400 indeed showed in vivo activity. Similarly, tricyclic indole-2-carboxylic acids having a zwitterionic moiety such as SM-31900 were also active in vivo. In fact, SM-18400 and SM-31900 exhibited efficacy in several animal stroke models using intravenous infusion protocols. The practical syntheses of SM-18400 and SM-31900 as well as the novel synthesis of moderately active glycine antagonists, tricyclic azakynurenic acids, were also developed.

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“…The synthesis of speradine C by Liu et al 42 In 2005, Baron and coworkers utilized the dehydration of -hydroxytryptophan-like species to prepare a library of selective glycine-site N-methyl-D-aspartate (NMDA) receptor antagonists. 43 The researchers found that diastereomeric mixtures of -hydroxy-and -trimethyl silyl (TMS) ether compounds 1.41a-b could be converted to the corresponding dehydrotryptophan-like species 1.42 upon the addition of either para-toluenesulfonic acid (pTsOH) or trifluoromethanesulfonic anhydride (Tf2O) in high yields (Scheme 1.18). Baron and coworkers also found that, in one scenario, attempted dehydration of an intermediate TMS ether resulted in a quantitative retro-aldol reaction when trifluoracetic acid (TFA) was used as the source of acid.…”

Section: Dehydrotryptophan Derivatives By Acid-catalyzed Elimination Of Water Fromhydroxytryptophanmentioning

confidence: 99%

Solid-Phase Total Synthesis of Dehydrotryptophan-Bearing Cyclic Peptides Tunicyclin B, Sclerotide A, CDA3a, and CDA4a using a Protected β-Hydroxytryptophan Building Block

2021

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CoMFA, Synthesis, and Pharmacological Evaluation of (E)-3-(2-Carboxy-2-arylvinyl)-4,6-dichloro-1H-indole-2-carboxylic Acids: 3-[2-(3-Aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic Acid, a Potent Selective Glycine-Site NMDA Receptor Antagonist

Cited by 29 publications

References 40 publications

Dual Allosteric Effect in Glycine/NMDA Receptor Antagonism: A Comparative QSAR Approach

Dual Allosteric Effect in Glycine/NMDA Receptor Antagonism: A Comparative QSAR Approach

Tricyclic Quinoxalinediones, Aza-kynurenic Acids, and Indole-2- Carboxylic Acids as In Vivo Active NMDA-Glycine Antagonists

Solid-Phase Total Synthesis of Dehydrotryptophan-Bearing Cyclic Peptides Tunicyclin B, Sclerotide A, CDA3a, and CDA4a using a Protected β-Hydroxytryptophan Building Block

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