Synthesis of 7‐Chloro‐2,3‐dihydro‐2‐[1‐(pyridinyl)alkyl]pyridazino [4,5‐b]quinoline‐1,4,10(5H)‐triones as NMDA Glycine‐Site Antagonists.

Brown, Dean G.; al., et

doi:10.1002/chin.200403138

Cited by 7 publications

(10 citation statements)

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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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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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“…A new series of these derivatives was reported by Astra Zeneca Pharmaceuticals in the attempt to ameliorate poor and undesiderable physical properties while preserving potency and selectivity for the Gly/NMDA binding site [70]. Some of the reported compounds possessed improved drug-like properties (water solubility, cellular permeability, oral absorption) though they were less potent in binding assays.…”

Section: Zd-9379mentioning

confidence: 98%

Competitive Gly/NMDA Receptor Antagonists

Catarzi¹,

Colotta²,

Varano

2006

CTMC

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Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) where it is involved in the physiological regulation of different processes. It has been well established that excessive endogenous Glu is associated with many acute and chronic neurodegenerative disorders such as cerebral ischemia, epilepsy, amiotrophic lateral sclerosis (ALS), Parkinson's and Alzheimer's diseases. In addition to the classical competitive glutamate receptor (GluR) antagonists, much effort has been directed toward the development of many different non-competitive antagonists of these receptors and, among them, compounds blocking the glycine site on the NMDA receptor complex (Gly/NMDA) have been widely investigated. Many Gly/NMDA receptor antagonists showed to be potential therapeutic agents in many neurological diseases such as stroke, epilepsy and neuropathic pain. Some of them, endowed also with favourable physicochemical properties and low secondary undesiderable effects, reached clinical trials.

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“…Para este estudio se tomaron las mismas moléculas analizadas por Yosa et al, (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), teniendo como objetivo evaluar el método CNDO que permite calcular de manera más rápida que los métodos usados por Yosa et al, de esta manera comparar los resultados aquí obtenidos con los llevados a cabo anteriormente usando el funcional de la densidad. La diferencia entre los estudios previos y los resultados aquí propuestos radica principalmente en que CNDO por ser un método de tipo semiempírico lleva a cabo los cálculos mucho más rápido que usando la teoría del funcional de la densidad, en cuyo caso podría calcular miles incluso millones de moléculas para la rápida evaluación y determinación de sustancias agonistas o antagonistas.…”

Section: Materiales Y Métodosunclassified

“…(µ VB ν) = δ (µ,ν)VAB [13] Donde: VAB es la energía de interacción de un electrón A en un orbital de valencia con su centro (núcleo + capa interna) de B. V AB es corregido en CNDO incluyendo la desigualdad de la atracción electrón-centro y la repulsión electrón-centro. […”

Section: Materiales Y Métodosunclassified

“…Se seleccionaron 168 compuestos con actividad agonista y antagonista sobre la subunidad NR1 (22 agonistas y 146 antagonistas) (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). A cada compuesto le fueron evaluadas algunas propiedades de tipo fisicoquímico y electrónico, usando para este último el método hamiltoniano semiempírico CNDO (del inglés Complete Neglect Differentiation Orbital).…”

Section: Introductionunclassified

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Métodos semiempíricos para la evaluación rápida de orbitales frontera en la clasificación de agonistas y antagonistas de la subunidad NR1 de los receptores iGluR-NMDA

et al. 2011

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ResumenLos receptores iGluR-NMDA poseen gran interés farmacológico debido a que están implicados en desórdenes neurodegenerativos y neurosiquiátricos incluso participan en procesos como plasticidad sináptica, esencial para la formación de la memoria. La subunidad NR1 de los iGluR-NMDA es fundamental para que este tipo de receptores se activen apropiadamente, de hecho muchos de los fármacos estudiados para los desórdenes anteriormente mencionados, están dirigidos específicamente a la subunidad NR1. Estudios previos han determinado que el orbital molecular de más baja energía (LUMO), puede ser usado como parámetro para estimar la actividad agonista o antagonista en la subunidad NR1. Objetivo. Evaluar el método semiempírico CNDO para el cálculo rápido de la energía LUMO, con la finalidad de crear un modelo sencillo para el diseño in silico de nuevos fármacos. Materiales y métodos. Fueron seleccionadas 168 moléculas entre agonistas y antagonistas de la subunidad NR1. La energía de cada estructura fue optimizada y posteriormente fueron calculadas las energías de los orbitales frontera, el LogP, la energía total, la capacidad de formar puentes de hidrógeno, la energía de unión y el momento dipolar. Resultados. Se demuestra que la energía LUMO es suficiente para discriminar entre moléculas agonistas y antagonistas de esta subunidad y que el método CNDO evalúa estas propiedades de manera rápida y eficiente. Conclusión. El método CNDO permite el cálculo rápido, generando a futuro procedimientos eficaces para la caracterización de fármacos potenciales que actúen sobre este sitio en particular.Palabras clave: iGluR-NMDA, LUMO, agonista, antagonista, CNDO. AbstractSemiempirical methods for the rapid evaluation of frontier orbitals in the classification of agonists and antagonists of the NR1 subunit of the iGluR-NMDA receptors. The ionotropic glutamate receptors activated by N-Methyl-D-Aspartate (iGluR-NMDA) are of great importance in pharmacology since they are involved in neurodegenerative and neuropsychiatric disorders; they even participate in processes such as synaptic plasticity that are essential for memory formation. Subunit NR1 iGluRs-NMDA is of paramount importance for the appropriate activation of this type of receptors; in fact, many of the pharmaceutical products studied for the abovementioned disorders are targeted specifically to the NR1 subunit. Previous studies have shown that the lowest energy unoccupied molecular orbital (LUMO) can be used as a parameter to estimate the agonist and antagonist activity of the NR1subunit. Objective. Evaluate the semiemprical method CNDO for the rapid calculation of the LUMO energy with the aim of preparing a simple model for the in silico design of new pharmacological substances. Materials and methods. 168 molecules with agonist and antagonist activity in the NR1 subunit were selected. Energy of each structure was optimized and then we calculated the energy of the frontier orbital, the LogP, total energy, capacity of forming hydrogen bonds, binding energy, and dipolar moment...

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Synthesis of 7‐Chloro‐2,3‐dihydro‐2‐[1‐(pyridinyl)alkyl]pyridazino [4,5‐b]quinoline‐1,4,10(5H)‐triones as NMDA Glycine‐Site Antagonists.

Cited by 7 publications

References 1 publication

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

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

Competitive Gly/NMDA Receptor Antagonists

Métodos semiempíricos para la evaluación rápida de orbitales frontera en la clasificación de agonistas y antagonistas de la subunidad NR1 de los receptores iGluR-NMDA

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