Inhibition of wild type NR2B receptor expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
None
|
68.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor ATD D101A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
83.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor ATD T103A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
85.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor ATD D104A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
75.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor ATD E106A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
74.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor ATD F176A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
84.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor ATD F182A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
72.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor ATD T233A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
84.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor ATD K234A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
85.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor ATD E236A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
83.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor Pre-M1 N542A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
73.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor Pre-M1 T544A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
69.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor Pre-M1 S546A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
64.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor Pre-M1 S548A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
76.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor Pre-M1 F550A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
62.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor Pre-M1 E552A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
77.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor Pre-M1 S555A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
72.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor Pre-M1 D557A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
75.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor Pre-M1 V558A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
71.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor M2 N615A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
66.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor M2 N616A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
72.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor M3c V640A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
71.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor M3c I641A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
84.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor M3c F642A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
75.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor M3c L643A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
90.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor M3c A644C mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
73.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor M3c S645A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
85.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor M3c Y646A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
74.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor M3c T647A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
89.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor M3c A648C mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
73.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor M3c L650A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
76.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor M3c A651T mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
72.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor M3c A652T mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
83.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor post-M3 M654A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
71.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor post-M3 I655A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
76.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor post-M3 Q656A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor post-M3 E657A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
61.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Inhibition of NR2B receptor post-M3 E658A mutant expressed in Xenopus oocytes assessed as NMDA current at 0.5 mM relative to control
|
Homo sapiens
|
65.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
Year : 2008
Volume : 51
Issue : 6
First Page : 1534
Last Page : 1545
Authors : Chang HR, Kuo CC.
Abstract : The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and T648(NR1)-T647(NR2B) (the two outer pairs), significantly decrease FBM binding. Moreover, double mutations involving either the inner or the outer pair always show cooperative (nonadditive) effects on FBM binding, whereas double mutations involving both inner and outer pairs always show additive (noncooperative) effects. Most interestingly, triple mutations of any three of the four critical residues essentially abolish the effect of FBM. These findings indicate that T648(NR1)/T647(NR2B) and V644(NR1)/L643(NR2B) act cooperatively to contribute directly to the "outer binding region" and "inner binding region" in the FBM binding site, respectively. The outer and inner binding regions, however, seem to contribute independently to FBM binding. We conclude that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Displacement of [35S]TBPS from Wistar rat brain GABAA receptor
|
Rattus norvegicus
|
95.0
nM
|
|
Journal : J. Med. Chem.
Title : Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) derivatives with a polar chain in position 16alpha: synthesis and activity.
Year : 2009
Volume : 52
Issue : 7
First Page : 2119
Last Page : 2125
Authors : Slavíková B, Kristofíková Z, Chodounská H, Budesínský M, Durán FJ, Veleiro AS, Burton G, Kasal A.
Abstract : The lipophilic nature of allopregnanolone prevents its user-friendly application in human medicine. On inspiration by previously prepared allopregnanolone with a 16alpha-bound tetraethylammonium salt, an attempt was made to produce allopregnanolone analogues with polar groups introduced into position 16alpha with the goal of increasing water solubility, brain accessibility, and potency of neuroactive steroids. The Michael addition to derivatives of pregn-16-en-20-one was the key reaction step. The link between the steroid skeleton and the new side chain was either a methylene group (when diethyl malonate was added) or an oxygen atom (when a hydroxy derivative was added). [(35)S]TBPS displacement was used to evaluate the products. Several carbamates (but not their parent alcohols) displaced TBPS from the picrotoxin binding site on GABA(A) receptors. Although none of them was more potent than the above ammonium salt, which stimulated this study, their nonionic nature should not prevent their passage into the brain.
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
4.88
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
37.11
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
7.68
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
15.31
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.17
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.01
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.05
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.01
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.17
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.05
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.