AMPA Receptor Antagonists

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Alba Chimirri - One of the best experts 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.

  • 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:

    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.

  • AMPA Receptor Antagonists as potential anticonvulsant drugs
    Current Topics in Medicinal Chemistry, 2005
    Co-Authors: Giovambattista De Sarro, Rosaria Gitto, Laura De Luca, Maria Letizia Barreca, Emilio Russo, Guido Ferreri Ibbadu, Alba Chimirri
    Abstract:

    Over the last years α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate Receptors (AMPARs) have been intensively studied owing to their crucial role in physiological and pathological processes. Efforts targeting AMPAR have been focused on identification of ligands as potential therapeutic agents useful in the prevention and treatment of a variety of neurological and non-neurological diseases. In particular, extensive work was addressed to the discovery of selective Antagonists some of which proved to be potent anticonvulsant agents.

Alessandro Galli - One of the best experts 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, Vittoria Colotta, Flavia Varano, Guido Filacchioni, Alessandro Galli, 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, Guido Filacchioni, Alessandro Galli, 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.

  • 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.

  • characterization of the mechanism of anticonvulsant activity for a selected set of putative AMPA Receptor Antagonists
    Bioorganic & Medicinal Chemistry Letters, 2003
    Co-Authors: S Grasso, Maria Zappala, Nicola Micale, Frank S Menniti, Chiara Costagli, Alessandro Galli, C De Micheli
    Abstract:

    Abstract A selected set of 1-aryl-7,8-methylenedioxy-2,3-benzodiazepin-4-ones and their analogues were evaluated for their ability to bind the competitive and noncompetitive sites of the AMPA Receptors complex as well as to the glycine site of the NMDA Receptors. The results put in evidence that most of the test compounds, despite a close structural similarity with GYKI 52466, possess a significantly different pharmacological profile.

Rosaria Gitto - One of the best experts 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.

  • 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.

  • 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:

    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.

Giovambattista De Sarro - One of the best experts 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.

  • 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.

  • 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:

    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.

  • new 7 8 ethylenedioxy 2 3 benzodiazepines as noncompetitive AMPA Receptor Antagonists
    Bioorganic & Medicinal Chemistry Letters, 2006
    Co-Authors: Maria Zappala, S Grasso, Nicola Micale, Alessia Pellicano, Frank S Menniti, Guido Ferreri, Giovambattista De Sarro, C De Micheli
    Abstract:

    Abstract A series of 1-aryl-3,5-dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-ones 2a–f, were synthesized and screened as anticonvulsant agents in DBA/2 mice against sound-induced seizures. The new compounds display anticonvulsant properties although the ED50 values are higher than those of prototypes 1-aryl-3,5-dihydro-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-ones (1) and GYKI 52466, well-known noncompetitive AMPA Receptor Antagonists. Functional tests were performed to evaluate the antagonistic activity at the AMPA and kainate Receptors.

  • AMPA Receptor Antagonists as potential anticonvulsant drugs
    Current Topics in Medicinal Chemistry, 2005
    Co-Authors: Giovambattista De Sarro, Rosaria Gitto, Laura De Luca, Maria Letizia Barreca, Emilio Russo, Guido Ferreri Ibbadu, Alba Chimirri
    Abstract:

    Over the last years α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate Receptors (AMPARs) have been intensively studied owing to their crucial role in physiological and pathological processes. Efforts targeting AMPAR have been focused on identification of ligands as potential therapeutic agents useful in the prevention and treatment of a variety of neurological and non-neurological diseases. In particular, extensive work was addressed to the discovery of selective Antagonists some of which proved to be potent anticonvulsant agents.

Vittoria Colotta - One of the best experts on this subject based on the ideXlab platform.

  • Competitive AMPA Receptor Antagonists.
    Medicinal Research Reviews, 2020
    Co-Authors: Daniela Catarzi, Vittoria Colotta, Flavia Varano
    Abstract:

    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 ischaemia, epilepsy, amiotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease. These data have consequently added great impetus to the research in this field. In fact, many Glu Receptor Antagonists acting at the N-methyl-D-aspartic acid (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), and/or kainic acid (KA) Receptors have been developed as research tools and potential therapeutic agents. Ligands showing competitive antagonistic action at the AMPA type of Glu Receptors were first reported in 1988, and the systemically active 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline (NBQX) was first shown to have useful therapeutic effects in animal models of neurological disease in 1990. Since then, the quinoxaline template has represented the backbone of various competitive AMPA Receptor Antagonists belonging to different classes which had been developed in order to increase potency, selectivity and water solubility, but also to prolong the "in vivo" action. Compounds that present better pharmacokinetic properties and less serious adverse effects with respect to the others previously developed are undergoing clinical evaluation. In the near future, the most important clinical application for the AMPA Receptor Antagonists will probably be as neuroprotectant in neurodegenerative diseases, such as epilepsy, for the treatment of patients not responding to current therapies. The present review reports the history of competitive AMPA Receptor Antagonists from 1988 up to today, providing a systematic coverage of both the open and patent literature.

  • 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, Vittoria Colotta, Flavia Varano, Guido Filacchioni, Alessandro Galli, 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, Guido Filacchioni, Alessandro Galli, 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.

  • competitive AMPA Receptor Antagonists
    Medicinal Research Reviews, 2007
    Co-Authors: Daniela Catarzi, Vittoria Colotta, Flavia Varano
    Abstract:

    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 ischaemia, epilepsy, amiotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease. These data have consequently added great impetus to the research in this field. In fact, many Glu Receptor Antagonists acting at the N-methyl-D-aspartic acid (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), and/or kainic acid (KA) Receptors have been developed as research tools and potential therapeutic agents. Ligands showing competitive antagonistic action at the AMPA type of Glu Receptors were first reported in 1988, and the systemically active 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline (NBQX) was first shown to have useful therapeutic effects in animal models of neurological disease in 1990. Since then, the quinoxaline template has represented the backbone of various competitive AMPA Receptor Antagonists belonging to different classes which had been developed in order to increase potency, selectivity and water solubility, but also to prolong the “in vivo” action. Compounds that present better pharmacokinetic properties and less serious adverse effects with respect to the others previously developed are undergoing clinical evaluation. In the near future, the most important clinical application for the AMPA Receptor Antagonists will probably be as neuroprotectant in neurodegenerative diseases, such as epilepsy, for the treatment of patients not responding to current therapies. The present review reports the history of competitive AMPA Receptor Antagonists from 1988 up to today, providing a systematic coverage of both the open and patent literature. © 2006 Wiley Periodicals, Inc.

  • 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.