3-(2-Carboxyindol-3-yl)propionic acid derivatives: antagonists of the strychnine-insensitive glycine receptor associated with the N-methyl-D-aspartate receptor complex

A filtration binding assay using [3H]dichlorokynurenic acid to label the glycine binding site on the N-methyl-D-aspartic acid receptor has been evaluated on rat cortical membranes. This ligand binds to a single population of binding sites following mass action kinetics with a KD of 29 nM and a capacity of 5.73 pmol (mg protein)-1. The pharmacological specificity of the binding site is identical to that previously reported for this binding site using [3H]glycine as a radioligand. Agonists showed lower affinity and antagonists higher affinity when [3H]dichlorokynurenic acid was used compared with [3H]glycine. The higher affinity of [3H]dichlorokynurenic acid compared with [3H]glycine make it the more suitable compound with which to label the glycine site.

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“…were synthesized according to published methods Salituro et al 1990). Other compounds and reagents were from Sigma Chemical Co., St Louis, USA.…”

Section: Methodsmentioning

confidence: 99%

A Rapid Filtration Assay for the Glycine Binding Site on the NMDA Receptor in Rat Cortical Membranes using [3H]Dichlorokynurenic Acid

Canton¹,

Doble²,

Miquet³

et al. 1992

Journal of Pharmacy and Pharmacology

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“…Indoles 85a-c were prepared utilizing the modified Japp-Klingemann reaction. 37 Selective reduction using excess BH 3 gave the corresponding alcohols which were then treated with a variety of aromatic alcohols under Mitsunobu conditions to afford the corresponding ether 86 . The ester was then saponified to give indoles 27-55 .…”

Section: Synthesismentioning

confidence: 99%

“…Coupling of ethyl 4-chloro-3-(3-hydroxypropyl)-1 H -indole-2-carboxylate 37 and 4-chloro-3-methylphenol yielded 49 . 1 H NMR (400MHz, d 6 -DMSO): δ (ppm) 1 H NMR (400MHz, d 6 -DMSO): δ 11.68 (s, 1H), 7.66.…”

Section: Chemistrymentioning

confidence: 99%

Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design

et al. 2012

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Myeloid cell leukemia-1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified two chemically distinct hit series that bind to different sites on Mcl-1. Members of the two fragment classes were merged together to produce lead compounds that bind to Mcl-1 with a dissociation constant of <100 nM with selectivity for Mcl-1 over Bcl-xL and Bcl-2. Structures of merged compounds when complexed to Mcl-1 were obtained by X-ray crystallography and provide detailed information about the molecular recognition of small-molecule ligands binding Mcl-1. The compounds represent starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers.

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“…Tricyclic Quinoxalinediones [28,[30][31][32] In the early 1990s, three structurally distinct antagonists of the NMDA-glycine site were known, including kynurenic acids such as 1 (DCKA) [33][34][35]42,43], indole-2-carboxylic acids such as 2 [36][37][38], and quinoxalinediones such as 3 (DCQX) [39][40][41]. The former two molecules were being extensively modified by several laboratories [44][45][46][47][48][49][50][51][52][53][54][55] at that time and antagonists with high affinity for the glycine site such as 4 (L-689,560) [25] and 5 (MDL 29,951) [56] were synthesized (Chart 1).…”

Section: The Structure-activity Relationships and The Pharmacology Ofmentioning

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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3-(2-Carboxyindol-3-yl)propionic acid derivatives: antagonists of the strychnine-insensitive glycine receptor associated with the N-methyl-D-aspartate receptor complex

Cited by 45 publications

References 3 publications

A Rapid Filtration Assay for the Glycine Binding Site on the NMDA Receptor in Rat Cortical Membranes using [3H]Dichlorokynurenic Acid

A Rapid Filtration Assay for the Glycine Binding Site on the NMDA Receptor in Rat Cortical Membranes using [3H]Dichlorokynurenic Acid

Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design

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

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