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AMPA Receptor Antagonists

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Alba Chimirri – 1st expert on this subject based on the ideXlab platform

  • Enhancement of anti-absence effects of ethosuximide by low doses of a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor antagonist in a genetic animal model of absence epilepsy
    Epilepsy & Behavior, 2008
    Co-Authors: Emilio Russo, Alba Chimirri, Rosaria Gitto, Rita Citraro, Giovambattista De Sarro, Salvatore De Fazio, Rosario Marra, Eugenio Donato Di Paola

    Abstract:

    Abstract N -Acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (THIQ-10c) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor antagonist that has been demonstrated to antagonize generalized tonic–clonic seizures in different animal models of epilepsy. In the study described here, we tested the potential effect of such a compound alone or co-administered with ethosuximide in a genetic animal model of absence epilepsy, the WAG/Rij rat. The intraperitoneal or intracerebroventricular microinjection of THIQ-10c alone was unable to significantly modify the number and duration of spike-and-wave discharges (SWDs). In contrast, intracerebroventricular administration of AMPA induced a dose-dependent increase in the number of SWDs. THIQ-10c dose-dependently antagonized this effect. Furthermore, co-administration of THIQ-1c with ethosuximide (50 mg/kg, intraperitoneally) was able to significantly increase the efficacy of the anti-absence drug. In conclusion, although noncompetitive AMPA Receptor Antagonists alone might not be useful in the treatment of absence epilepsy because of their low therapeutic index, combining them with ethosuximide might be helpful in controlling absence seizures in patients not tolerating this drug or in refractory patients.

  • synthesis and anticonvulsant evaluation of n substituted isoquinoline AMPA Receptor Antagonists
    Bioorganic & Medicinal Chemistry, 2008
    Co-Authors: Rosaria Gitto, Laura De Luca, Benedetta Pagano, Rita Citraro, Giovanbattista De Sarro, Lara Costa, Lucia Ciranna, Alba Chimirri

    Abstract:

    Abstract In our previous studies a ligand-based approach led to the identification of noncompetitive AMPA Receptor Antagonists containing isoquinoline scaffold. In an attempt to perform a systematic SAR study, we synthesized new N-substituted-isoquinolines bearing the most salient features described by our 3D pharmacophore model. All compounds were screened against audiogenic seizures and some derivatives showed anticonvulsant properties. Compound 24 , the most active of the series, was also tested in vitro using the patch–clamp technique and proved to antagonize AMPA-mediated effects.

  • effects of non competitive AMPA Receptor Antagonists injected into some brain areas of wag rij rats an animal model of generalized absence epilepsy
    Neuropharmacology, 2006
    Co-Authors: Rita Citraro, Alba Chimirri, Rosaria Gitto, Emilio Russo, Santo Gratteri, Eugenio Donato Di Paola, Guido Ferreri Ibbadu, Carmela Curinga, Giuseppe Donato, Giovambattista De Sarro

    Abstract:

    Abstract CFM-2 [1-(4-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one] and THIQ-10c [N-acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline], are two non-competitive 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) Receptor Antagonists, which demonstrated to antagonize generalized tonic-clonic seizures in different animal models. We have evaluated the effects of such compounds in a genetic animal model of absence epilepsy, the WAG/Rij rat. Animals were focally microinjected into specific brain areas of the cortico-thalamic circuit in order to evaluate the effects of these compounds on the number and duration of epileptic spike-wave discharges (SWDs) and better characterize the role of AMPA neurotransmission in this animal model. The focal microinjection of the two AMPA Antagonists into some thalamic nuclei (ventralis posteromedialis (VPM), reticularis (NRT), ventralis posterolateralis (VPL) and the primary somatosensory forelimb region (S1FL)) was, generally, not able to significantly modify the occurrence of SWDs. Whereas, both compounds were able to reduce the number and duration of SWDs dose-dependently when microinjected into the peri-oral region of the primary somatosensory cortex (S1po). These findings suggest that AMPA Receptor Antagonists might play a role in absence epilepsies and that it might depend on the involvement of specific neuronal areas.

Alessandro Galli – 2nd expert on this subject based on the ideXlab platform

  • synthesis and biological evaluation of novel 9 heteroaryl substituted 7 chloro 4 5 dihydro 4 oxo 1 2 4 triazolo 1 5 a quinoxaline 2 carboxylates tqx as r s 2 amino 3 3 hydroxy 5 methylisoxazol 4 yl propionic acid AMPA Receptor Antagonists
    Chemical & Pharmaceutical Bulletin, 2008
    Co-Authors: Daniela Catarzi, Flavia Varano, Vittoria Colotta, Alessandro Galli, Guido Filacchioni, Paola Gratteri, Jacopo Sgrignani, Chiara Costagli

    Abstract:

    : In this paper, we report a study on some new 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylate derivatives (TQXs), bearing a nitrogen-containing heterocycle at position-9, and designed as (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) Receptor Antagonists. These compounds ensue from the structural modification of previously reported 8-heteroaryl-TQXs which were endowed with high affinity and selectivity for the AMPA Receptor. All the newly synthesized compounds were biologically evaluated for their binding at the AMPA Receptor. Gly/N-methyl-D-aspartic acid (NMDA) and kainic acid (KA) high-affinity binding assays were performed to assess the selectivity of the reported derivatives toward the AMPA Receptor. This study produced some new TQXs which are less potent than the reference compounds, and endowed with a mixed AMPA and Gly/NMDA Receptor binding affinity. To rationalize the experimental findings, a molecular modeling study was performed by docking some TQX derivatives to the AMPA Receptor model.

  • novel AMPA and kainate Receptor Antagonists containing the pyrazolo 1 5 c quinazoline ring system synthesis and structure activity relationships
    Bioorganic & Medicinal Chemistry, 2008
    Co-Authors: Flavia Varano, Daniela Catarzi, Vittoria Colotta, Alessandro Galli, Guido Filacchioni, Ombretta Lenzi, Chiara Costagli

    Abstract:

    Abstract This paper reports the synthesis and AMPA, Gly/NMDA, and KA Receptor binding affinities of a new set of 1,9-disubstituted-8-chloro-pyrazolo[1,5- c ]quinazoline-2-carboxylates 2 – 34 . Binding data show that, in general, compounds 2 – 34 bind to the AMPA Receptor with good affinity and selectivity. In particular, the obtained results indicate that the contemporary presence of a 1,2-dicarboxylic acid moiety and suitable benzo-substituents on the PQZ system is important to gain selective AMPA Receptor Antagonists. Moreover, this study shows that the presence of a 2-carboxybenzoylamino substituent at position-9 (compounds 33 – 34 ) is important for obtaining selective KA Receptor Antagonists. Some selected compounds were also tested for their functional antagonistic activity at both AMPA and NMDA Receptor-ion channels.

  • 3-hydroxy-quinazoline-2,4-dione as a useful scaffold to obtain selective Gly/NMDA and AMPA Receptor Antagonists.
    Bioorganic & Medicinal Chemistry Letters, 2004
    Co-Authors: Vittoria Colotta, Daniela Catarzi, Flavia Varano, Francesca Romana Calabri, Guido Filacchioni, Chiara Costagli, Alessandro Galli

    Abstract:

    The synthesis and Gly/NMDA, AMPA and KA Receptor binding activities of some 3-hydroxy-quinazoline-2,4-dione derivatives are reported. The binding data, together with functional antagonism studies, showed that the 3-hydroxy-quinazoline-2,4-dione moiety can be considered a useful scaffold to obtain selective Gly/NMDA and AMPA Receptor Antagonists. In fact, introduction of chlorine atom(s) on precise position(s) of the benzofused moiety yielded Gly/NMDA selective Antagonists, while the presence of the 6-(1,2,4-triazol-4-yl) group shifted the affinity and selectivity towards the AMPA Receptor.

Rosaria Gitto – 3rd expert on this subject based on the ideXlab platform

  • improvement of water solubility of non competitive AMPA Receptor Antagonists by complexation with β cyclodextrin
    Bioorganic & Medicinal Chemistry, 2008
    Co-Authors: Rosanna Stancanelli, Rosaria Gitto, Laura De Luca, Vincenza Crupi, P Ficarra, R Ficarra, M Guardo, Nunzio Iraci, D Majolino, S Tommasini

    Abstract:

    Abstract The ( R ,  S )-2-acetyl-1-(4′-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (( R ,  S )- 1 ) was previously identified as a potent non-competitive AMPA Receptor antagonist able to prevent epileptic seizures and reduce AMPA-induced current in electrophysiological experiments. Through the enantiomeric resolution of racemate by chiral HPLC we already demonstrated that the ( R )- 1 enantiomer was the eutomer. Considering the poor water solubility, these compounds have been complexed with β-cyclodextrin (β-CyD). The effect of β-cyclodextrin on the spectral features of molecules was quantitatively investigated, in fully aqueous medium by phase-solubility study and the obtained diagrams suggested that it forms complexes with a molar ratio 1:1. The binding constant ( K ( R )- 1  = 15889 M −1 , K ( R ,  S )- 1  = 1079 M −1 ) and the complexation efficiency (CE) were calculated. Then the solid complexes in 1:1 molar ratio were prepared by the co-precipitation method and the FTIR-ATR measurements were carried out in order to confirm the host–guest interactions that drive the complexation process, by monitoring the significant differences of the spectra of the complexes with respect to those of the corresponding physical mixtures in the same molar ratio. The experimental data have been compared with molecular modelling studies and we confirmed our hypothesis.

  • Enhancement of anti-absence effects of ethosuximide by low doses of a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor antagonist in a genetic animal model of absence epilepsy
    Epilepsy & Behavior, 2008
    Co-Authors: Emilio Russo, Alba Chimirri, Rosaria Gitto, Rita Citraro, Giovambattista De Sarro, Salvatore De Fazio, Rosario Marra, Eugenio Donato Di Paola

    Abstract:

    Abstract N -Acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (THIQ-10c) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor antagonist that has been demonstrated to antagonize generalized tonic–clonic seizures in different animal models of epilepsy. In the study described here, we tested the potential effect of such a compound alone or co-administered with ethosuximide in a genetic animal model of absence epilepsy, the WAG/Rij rat. The intraperitoneal or intracerebroventricular microinjection of THIQ-10c alone was unable to significantly modify the number and duration of spike-and-wave discharges (SWDs). In contrast, intracerebroventricular administration of AMPA induced a dose-dependent increase in the number of SWDs. THIQ-10c dose-dependently antagonized this effect. Furthermore, co-administration of THIQ-1c with ethosuximide (50 mg/kg, intraperitoneally) was able to significantly increase the efficacy of the anti-absence drug. In conclusion, although noncompetitive AMPA Receptor Antagonists alone might not be useful in the treatment of absence epilepsy because of their low therapeutic index, combining them with ethosuximide might be helpful in controlling absence seizures in patients not tolerating this drug or in refractory patients.

  • synthesis and anticonvulsant evaluation of n substituted isoquinoline AMPA Receptor Antagonists
    Bioorganic & Medicinal Chemistry, 2008
    Co-Authors: Rosaria Gitto, Laura De Luca, Benedetta Pagano, Rita Citraro, Giovanbattista De Sarro, Lara Costa, Lucia Ciranna, Alba Chimirri

    Abstract:

    Abstract In our previous studies a ligand-based approach led to the identification of noncompetitive AMPA Receptor Antagonists containing isoquinoline scaffold. In an attempt to perform a systematic SAR study, we synthesized new N-substituted-isoquinolines bearing the most salient features described by our 3D pharmacophore model. All compounds were screened against audiogenic seizures and some derivatives showed anticonvulsant properties. Compound 24 , the most active of the series, was also tested in vitro using the patch–clamp technique and proved to antagonize AMPA-mediated effects.