|
Binding affinity of compound was determined against Glutamate receptor (KA2) using cell membranes prepared from HEK293 cells
|
None
|
750.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Alkylidenyl glutamic acids, potent and selective GluR5 agonists.
Year : 2000
Volume : 10
Issue : 16
First Page : 1807
Last Page : 1810
Authors : Baker SR, Bleakman D, Ezquerra J, Ballyk BA, Deverill M, Ho K, Kamboj RK, Collado I, Domínguez C, Escribano A, Mateo AI, Pedregal C, Rubio A.
Abstract : Twenty-four 4-alkylidene glutamic acids were synthesised and tested as potential subtype selective GluR5 and 6 ligands. It was found that a critical size of alkylidene group gave potent and selective GluR5 receptor agonists. LY339624 had Kis of 0.0326 and >100 microM on GluR5 and 6 receptors, respectively.
|
The effective concentration for 50% glutamate response was measured on Group II Metabotropic glutamate receptor
|
None
|
290.0
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacophore models of group I and group II metabotropic glutamate receptor agonists. Analysis of conformational, steric, and topological parameters affecting potency and selectivity.
Year : 1999
Volume : 42
Issue : 15
First Page : 2816
Last Page : 2827
Authors : Costantino G, Macchiarulo A, Pellicciari R.
Abstract : A wide variety of conformationally constrained glutamate analogues, active as group I or group II metabotropic glutamate receptor agonists, were employed in a molecular modeling study aimed at the definition of group I and group II agonist pharmacophoric models. The results of this study can be summarized as follows: (i) Recognition sites of both group I and group II mGluRs can adequately be described by five-point pharmacophores. (ii) An extended conformation of glutamate is required for interaction with both group I and group II mGluRs. Group I receptors, however, can also be activated by a more folded conformation if only four pharmacophore points are considered. (iii) Conformational preferences are, however, not sufficient to explain the potency and selectivity of the whole set of ligands. Volume comparison analysis allowed us to define steric environments for group I and group II mGluRs. Group I mGluRs are characterized by a region of allowed volume in proximity of the distal acidic function, whereas group II mGluRs are characterized by a small polar pocket whose occupancy confers high potency and selectivity. Finally, our study points out the necessity of a careful analysis of the energetic requirements needed to attain the putative bioactive conformations and of explicitly considering the conformational mobility of carboxylate groups.
|
Binding affinity was measured by [3H]- Ionotropic glutamate receptor AMPA binding assay.
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Heterocyclic excitatory amino acids. Synthesis and biological activity of novel analogues of AMPA.
Year : 1992
Volume : 35
Issue : 1
First Page : 107
Last Page : 111
Authors : Madsen U, Wong EH.
Abstract : The novel acidic amino acids 6a-c, 7, and 8 have been synthesized via 1,3-dipolar cycloadditions, using nitrile oxides and alkynes. The prepared compounds are heterocyclic analogues of glutamic acid with differing chain lengths. One of these compounds, (RS)-2-amino-3-(3-carboxy-5-methyl-4- isoxazolyl)propionic acid (ACPA, 8), was shown in [3H]AMPA binding studies to be more active than AMPA itself (IC50 = 20 nM compared to IC50 = 79 nM for AMPA). No affinity for NMDA receptors (NMDA-sensitive [3H]glutamic acid binding) was found, and only weak affinity in [3H]kainic acid binding (IC50 = 6.3 microM) was detected. The excitatory activity in rat cortical wedge also showed that ACPA was more potent than AMPA (EC50 = 1.0 microM compared to EC50 = 3.5 microM for AMPA). The depolarizing effect of ACPA could be fully antagonized by the selective non-NMDA antagonist 6-cyano-7-nitro-quinoxazoline-2,3-dione (CNQX), but was unaffected by the selective NMDA antagonist D-2-amino-5-phosphonovaleric acid (AP5).
|
Compound was evaluated for the inhibition of [3H]AMPA binding to Ionotropic glutamate receptor AMPA from rat brain synaptic membrane.
|
None
|
150.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses of trans-3-substituted-CCG-IV analogs and their characterization to ionotropic glutamate receptors
Year : 1996
Volume : 6
Issue : 20
First Page : 2381
Last Page : 2386
Authors : Shimamoto K, Shigeri Y, Nakajima T, Yumoto N, Yoshikawa S, Ohfune Y
|
Displacement of [3H]AMPA from human Ionotropic glutamate receptor AMPA 2 expressed in HEK293 cells
|
Homo sapiens
|
940.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of willardiine and 6-azawillardiine analogs: pharmacological characterization on cloned homomeric human AMPA and kainate receptor subtypes.
Year : 1997
Volume : 40
Issue : 22
First Page : 3645
Last Page : 3650
Authors : Jane DE, Hoo K, Kamboj R, Deverill M, Bleakman D, Mandelzys A.
Abstract : Both willardiine and azawillardiine analogs (18-28) have been reported to be potent and selective agonists for either AMPA or kainate receptors. We report here the novel synthesis and pharmacological characterization of a range of willardiine (18-23) and 6-azawillardiine (24-28) analogs on cells individually expressing human homomeric hGluR1, hGluR2, hGluR4, or hGluR5 receptors. Reaction of the sodium salts of substituted uracils (7-12) or 6-azauracils (13-16) with (S)-3-[(tert-butoxycarbonyl)amino]oxetan-2-one (17) in dry DMF, subsequent deprotection in TFA, and purification by ion-exchange chromatography gave mainly the willardiine analog in which alkylation took place on N1 of the uracil ring. We have investigated the subtype selectivity of these compounds by examining their binding affinity for homomeric hGluR1, -2, -4, or -5 (and hGluR6 in the case of 5-iodowillardiine (22)). From this study we have demonstrated that 22 has high affinity for hGluR5 and, compared to kainate, displays excellent selectivity for this receptor over both the AMPA receptor subtypes and the homomeric kainate receptor, hGluR6. 5-Fluorowillardiine (19) has higher affinity than AMPA for both homomeric hGluR1 and hGluR2 and compared to AMPA displays greater selectivity for AMPA receptor subtypes over the kainate receptor, hGluR5. Some structural features required for optimal activity at homomeric AMPA or kainate receptor subtypes have also been identified. It would appear that quite large lipophilic substituents at the 5-position of the uracil ring not only are accommodated by hGluR5 receptors but also lead to enhanced affinity for these receptors. In contrast to this, for optimal binding affinity to hGluR1, -2, or -4, smaller, electron-withdrawing substituents are required. For optimal activity at hGluR4 receptors a 6-aza-substituted willardiine is favored. The subtype-selective compounds described here are likely to be useful tools to probe the distribution and the physiological roles of the various glutamate receptor subunits in the central nervous system.
|
Binding affinity of compound was determined against Ionotropic glutamate receptor AMPA 2 using cell membranes prepared from HEK293 cells
|
None
|
940.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Alkylidenyl glutamic acids, potent and selective GluR5 agonists.
Year : 2000
Volume : 10
Issue : 16
First Page : 1807
Last Page : 1810
Authors : Baker SR, Bleakman D, Ezquerra J, Ballyk BA, Deverill M, Ho K, Kamboj RK, Collado I, Domínguez C, Escribano A, Mateo AI, Pedregal C, Rubio A.
Abstract : Twenty-four 4-alkylidene glutamic acids were synthesised and tested as potential subtype selective GluR5 and 6 ligands. It was found that a critical size of alkylidene group gave potent and selective GluR5 receptor agonists. LY339624 had Kis of 0.0326 and >100 microM on GluR5 and 6 receptors, respectively.
|
Compound was tested for binding affinity against human Ionotropic glutamate receptor AMPA 2 in HK293 cells using [3H]AMPA as radioligand
|
None
|
940.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-Alkyl- and 4-cinnamylglutamic acid analogues are potent GluR5 kainate receptor agonists.
Year : 2000
Volume : 43
Issue : 10
First Page : 1958
Last Page : 1968
Authors : Pedregal C, Collado I, Escribano A, Ezquerra J, Domínguez C, Mateo AI, Rubio A, Baker SR, Goldsworthy J, Kamboj RK, Ballyk BA, Hoo K, Bleakman D.
Abstract : Enantiomerically pure (2S,4R)-4-substituted glutamic acids were prepared and tested for homomeric GluR5 and GluR6 kainate subtype receptor affinity. Some of the 4-cinnamyl analogues showed high selectivity and potency (K(i) < 25 nM) for the GluR5 receptors. The greatest selectivity and potency were achieved with the 3-(2-naphthyl)prop-2-enyl compound. This compound, LY339434, has negligible activity at the AMPA and kainate receptors GluR1, -2, -4 and -6. Although, LY339434 shows agonist activity at NMDA receptors in cultural hippocampal neurons (approximate EC(50) of 2.5 microM), we consider that LY339434 should be a useful pharmacological tool for the investigation of the functional role of GluR5 kainate receptors.
|
Displacement of [3H]AMPA from human Ionotropic glutamate receptor AMPA 4 expressed in HEK293 cells
|
Homo sapiens
|
868.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of willardiine and 6-azawillardiine analogs: pharmacological characterization on cloned homomeric human AMPA and kainate receptor subtypes.
Year : 1997
Volume : 40
Issue : 22
First Page : 3645
Last Page : 3650
Authors : Jane DE, Hoo K, Kamboj R, Deverill M, Bleakman D, Mandelzys A.
Abstract : Both willardiine and azawillardiine analogs (18-28) have been reported to be potent and selective agonists for either AMPA or kainate receptors. We report here the novel synthesis and pharmacological characterization of a range of willardiine (18-23) and 6-azawillardiine (24-28) analogs on cells individually expressing human homomeric hGluR1, hGluR2, hGluR4, or hGluR5 receptors. Reaction of the sodium salts of substituted uracils (7-12) or 6-azauracils (13-16) with (S)-3-[(tert-butoxycarbonyl)amino]oxetan-2-one (17) in dry DMF, subsequent deprotection in TFA, and purification by ion-exchange chromatography gave mainly the willardiine analog in which alkylation took place on N1 of the uracil ring. We have investigated the subtype selectivity of these compounds by examining their binding affinity for homomeric hGluR1, -2, -4, or -5 (and hGluR6 in the case of 5-iodowillardiine (22)). From this study we have demonstrated that 22 has high affinity for hGluR5 and, compared to kainate, displays excellent selectivity for this receptor over both the AMPA receptor subtypes and the homomeric kainate receptor, hGluR6. 5-Fluorowillardiine (19) has higher affinity than AMPA for both homomeric hGluR1 and hGluR2 and compared to AMPA displays greater selectivity for AMPA receptor subtypes over the kainate receptor, hGluR5. Some structural features required for optimal activity at homomeric AMPA or kainate receptor subtypes have also been identified. It would appear that quite large lipophilic substituents at the 5-position of the uracil ring not only are accommodated by hGluR5 receptors but also lead to enhanced affinity for these receptors. In contrast to this, for optimal binding affinity to hGluR1, -2, or -4, smaller, electron-withdrawing substituents are required. For optimal activity at hGluR4 receptors a 6-aza-substituted willardiine is favored. The subtype-selective compounds described here are likely to be useful tools to probe the distribution and the physiological roles of the various glutamate receptor subunits in the central nervous system.
|
Binding affinity of compound was determined against Ionotropic glutamate receptor AMPA 4 using cell membranes prepared from HEK293 cells
|
None
|
868.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Alkylidenyl glutamic acids, potent and selective GluR5 agonists.
Year : 2000
Volume : 10
Issue : 16
First Page : 1807
Last Page : 1810
Authors : Baker SR, Bleakman D, Ezquerra J, Ballyk BA, Deverill M, Ho K, Kamboj RK, Collado I, Domínguez C, Escribano A, Mateo AI, Pedregal C, Rubio A.
Abstract : Twenty-four 4-alkylidene glutamic acids were synthesised and tested as potential subtype selective GluR5 and 6 ligands. It was found that a critical size of alkylidene group gave potent and selective GluR5 receptor agonists. LY339624 had Kis of 0.0326 and >100 microM on GluR5 and 6 receptors, respectively.
|
Compound was tested for binding affinity against human Ionotropic glutamate receptor AMPA 4 in HEK293 cells using [3H]AMPA as radioligand
|
None
|
868.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-Alkyl- and 4-cinnamylglutamic acid analogues are potent GluR5 kainate receptor agonists.
Year : 2000
Volume : 43
Issue : 10
First Page : 1958
Last Page : 1968
Authors : Pedregal C, Collado I, Escribano A, Ezquerra J, Domínguez C, Mateo AI, Rubio A, Baker SR, Goldsworthy J, Kamboj RK, Ballyk BA, Hoo K, Bleakman D.
Abstract : Enantiomerically pure (2S,4R)-4-substituted glutamic acids were prepared and tested for homomeric GluR5 and GluR6 kainate subtype receptor affinity. Some of the 4-cinnamyl analogues showed high selectivity and potency (K(i) < 25 nM) for the GluR5 receptors. The greatest selectivity and potency were achieved with the 3-(2-naphthyl)prop-2-enyl compound. This compound, LY339434, has negligible activity at the AMPA and kainate receptors GluR1, -2, -4 and -6. Although, LY339434 shows agonist activity at NMDA receptors in cultural hippocampal neurons (approximate EC(50) of 2.5 microM), we consider that LY339434 should be a useful pharmacological tool for the investigation of the functional role of GluR5 kainate receptors.
|
Binding affinity of compound was determined against Ionotropic glutamate receptor ionotropic kainate 1 using cell membranes prepared from HEK293 cells
|
None
|
701.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Alkylidenyl glutamic acids, potent and selective GluR5 agonists.
Year : 2000
Volume : 10
Issue : 16
First Page : 1807
Last Page : 1810
Authors : Baker SR, Bleakman D, Ezquerra J, Ballyk BA, Deverill M, Ho K, Kamboj RK, Collado I, Domínguez C, Escribano A, Mateo AI, Pedregal C, Rubio A.
Abstract : Twenty-four 4-alkylidene glutamic acids were synthesised and tested as potential subtype selective GluR5 and 6 ligands. It was found that a critical size of alkylidene group gave potent and selective GluR5 receptor agonists. LY339624 had Kis of 0.0326 and >100 microM on GluR5 and 6 receptors, respectively.
|
Binding affinity against human ionotropic glutamate receptor kainate 1 in HK293 cells using [3H]kainate as radioligand
|
None
|
701.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-Alkyl- and 4-cinnamylglutamic acid analogues are potent GluR5 kainate receptor agonists.
Year : 2000
Volume : 43
Issue : 10
First Page : 1958
Last Page : 1968
Authors : Pedregal C, Collado I, Escribano A, Ezquerra J, Domínguez C, Mateo AI, Rubio A, Baker SR, Goldsworthy J, Kamboj RK, Ballyk BA, Hoo K, Bleakman D.
Abstract : Enantiomerically pure (2S,4R)-4-substituted glutamic acids were prepared and tested for homomeric GluR5 and GluR6 kainate subtype receptor affinity. Some of the 4-cinnamyl analogues showed high selectivity and potency (K(i) < 25 nM) for the GluR5 receptors. The greatest selectivity and potency were achieved with the 3-(2-naphthyl)prop-2-enyl compound. This compound, LY339434, has negligible activity at the AMPA and kainate receptors GluR1, -2, -4 and -6. Although, LY339434 shows agonist activity at NMDA receptors in cultural hippocampal neurons (approximate EC(50) of 2.5 microM), we consider that LY339434 should be a useful pharmacological tool for the investigation of the functional role of GluR5 kainate receptors.
|
Displacement of [3H]kainate from human Ionotropic glutamate receptor ionotropic kainate 1 expressed in HEK293 cells
|
Homo sapiens
|
701.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of willardiine and 6-azawillardiine analogs: pharmacological characterization on cloned homomeric human AMPA and kainate receptor subtypes.
Year : 1997
Volume : 40
Issue : 22
First Page : 3645
Last Page : 3650
Authors : Jane DE, Hoo K, Kamboj R, Deverill M, Bleakman D, Mandelzys A.
Abstract : Both willardiine and azawillardiine analogs (18-28) have been reported to be potent and selective agonists for either AMPA or kainate receptors. We report here the novel synthesis and pharmacological characterization of a range of willardiine (18-23) and 6-azawillardiine (24-28) analogs on cells individually expressing human homomeric hGluR1, hGluR2, hGluR4, or hGluR5 receptors. Reaction of the sodium salts of substituted uracils (7-12) or 6-azauracils (13-16) with (S)-3-[(tert-butoxycarbonyl)amino]oxetan-2-one (17) in dry DMF, subsequent deprotection in TFA, and purification by ion-exchange chromatography gave mainly the willardiine analog in which alkylation took place on N1 of the uracil ring. We have investigated the subtype selectivity of these compounds by examining their binding affinity for homomeric hGluR1, -2, -4, or -5 (and hGluR6 in the case of 5-iodowillardiine (22)). From this study we have demonstrated that 22 has high affinity for hGluR5 and, compared to kainate, displays excellent selectivity for this receptor over both the AMPA receptor subtypes and the homomeric kainate receptor, hGluR6. 5-Fluorowillardiine (19) has higher affinity than AMPA for both homomeric hGluR1 and hGluR2 and compared to AMPA displays greater selectivity for AMPA receptor subtypes over the kainate receptor, hGluR5. Some structural features required for optimal activity at homomeric AMPA or kainate receptor subtypes have also been identified. It would appear that quite large lipophilic substituents at the 5-position of the uracil ring not only are accommodated by hGluR5 receptors but also lead to enhanced affinity for these receptors. In contrast to this, for optimal binding affinity to hGluR1, -2, or -4, smaller, electron-withdrawing substituents are required. For optimal activity at hGluR4 receptors a 6-aza-substituted willardiine is favored. The subtype-selective compounds described here are likely to be useful tools to probe the distribution and the physiological roles of the various glutamate receptor subunits in the central nervous system.
|
Ability to bind to Ionotropic glutamate receptor ionotropic kainate 3 was evaluated
|
None
|
789.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-Alkyl- and 4-cinnamylglutamic acid analogues are potent GluR5 kainate receptor agonists.
Year : 2000
Volume : 43
Issue : 10
First Page : 1958
Last Page : 1968
Authors : Pedregal C, Collado I, Escribano A, Ezquerra J, Domínguez C, Mateo AI, Rubio A, Baker SR, Goldsworthy J, Kamboj RK, Ballyk BA, Hoo K, Bleakman D.
Abstract : Enantiomerically pure (2S,4R)-4-substituted glutamic acids were prepared and tested for homomeric GluR5 and GluR6 kainate subtype receptor affinity. Some of the 4-cinnamyl analogues showed high selectivity and potency (K(i) < 25 nM) for the GluR5 receptors. The greatest selectivity and potency were achieved with the 3-(2-naphthyl)prop-2-enyl compound. This compound, LY339434, has negligible activity at the AMPA and kainate receptors GluR1, -2, -4 and -6. Although, LY339434 shows agonist activity at NMDA receptors in cultural hippocampal neurons (approximate EC(50) of 2.5 microM), we consider that LY339434 should be a useful pharmacological tool for the investigation of the functional role of GluR5 kainate receptors.
|
Binding affinity of compound was determined against Ionotropic glutamate receptor ionotropic kainate 3 using cell membranes prepared from HEK293 cells
|
None
|
789.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Alkylidenyl glutamic acids, potent and selective GluR5 agonists.
Year : 2000
Volume : 10
Issue : 16
First Page : 1807
Last Page : 1810
Authors : Baker SR, Bleakman D, Ezquerra J, Ballyk BA, Deverill M, Ho K, Kamboj RK, Collado I, Domínguez C, Escribano A, Mateo AI, Pedregal C, Rubio A.
Abstract : Twenty-four 4-alkylidene glutamic acids were synthesised and tested as potential subtype selective GluR5 and 6 ligands. It was found that a critical size of alkylidene group gave potent and selective GluR5 receptor agonists. LY339624 had Kis of 0.0326 and >100 microM on GluR5 and 6 receptors, respectively.
|
Ability to bind to Ionotropic glutamate receptor kainate (kainate 2) was evaluated.
|
None
|
750.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-Alkyl- and 4-cinnamylglutamic acid analogues are potent GluR5 kainate receptor agonists.
Year : 2000
Volume : 43
Issue : 10
First Page : 1958
Last Page : 1968
Authors : Pedregal C, Collado I, Escribano A, Ezquerra J, Domínguez C, Mateo AI, Rubio A, Baker SR, Goldsworthy J, Kamboj RK, Ballyk BA, Hoo K, Bleakman D.
Abstract : Enantiomerically pure (2S,4R)-4-substituted glutamic acids were prepared and tested for homomeric GluR5 and GluR6 kainate subtype receptor affinity. Some of the 4-cinnamyl analogues showed high selectivity and potency (K(i) < 25 nM) for the GluR5 receptors. The greatest selectivity and potency were achieved with the 3-(2-naphthyl)prop-2-enyl compound. This compound, LY339434, has negligible activity at the AMPA and kainate receptors GluR1, -2, -4 and -6. Although, LY339434 shows agonist activity at NMDA receptors in cultural hippocampal neurons (approximate EC(50) of 2.5 microM), we consider that LY339434 should be a useful pharmacological tool for the investigation of the functional role of GluR5 kainate receptors.
|
Binding affinity against Ionotropic glutamate receptor kainate by displacing [3H]KA from purified rat synaptic membranes
|
None
|
350.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity studies on excitatory amino acids structurally related to ibotenic acid.
Year : 1985
Volume : 28
Issue : 5
First Page : 673
Last Page : 679
Authors : Krogsgaard-Larsen P, Brehm L, Johansen JS, Vinzents P, Lauridsen J, Curtis DR.
Abstract : With use of ibotenic acid as a lead, analogues of (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and of (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA) were synthesized and tested as excitants of neurons in the cat spinal cord by using microelectrophoretic techniques and as inhibitors of the binding of kainic acid in vitro. Like AMPA and 7-HPCA, (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridine-5-carboxylic acid (10, 5-HPCA) and (RS)-3-hydroxy-5-(bromomethyl)isoxazole-4-propionic acid (11, ABPA) proved to interact potently and selectively with central quisqualic acid receptors, assumed to represent physiological glutamic acid receptors. Analogues of 7-HPCA or 10, in which one or both of the acid groups were masked, were very weak or inactive as neuronal excitants and had no antagonistic effects at excitatory amino acid receptors. The structure of 7-HPCA in the crystalline state was established by X-ray analyses. The preferred conformation of 10 in aqueous solution was determined by 1H NMR spectroscopy. On the basis of these studies, 7-HPCA as well as 10 were shown to adopt preferentially conformations with the carboxylate groups in equatorial positions. It is suggested that AMPA, 7-HPCA, and 10 interact with quisqualic acid receptors in conformations essentially reflecting active conformation(s) of glutamic acid at these receptors.
|
Binding affinity was measured by [3H]- KAIN receptor binding assay.
|
None
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : Heterocyclic excitatory amino acids. Synthesis and biological activity of novel analogues of AMPA.
Year : 1992
Volume : 35
Issue : 1
First Page : 107
Last Page : 111
Authors : Madsen U, Wong EH.
Abstract : The novel acidic amino acids 6a-c, 7, and 8 have been synthesized via 1,3-dipolar cycloadditions, using nitrile oxides and alkynes. The prepared compounds are heterocyclic analogues of glutamic acid with differing chain lengths. One of these compounds, (RS)-2-amino-3-(3-carboxy-5-methyl-4- isoxazolyl)propionic acid (ACPA, 8), was shown in [3H]AMPA binding studies to be more active than AMPA itself (IC50 = 20 nM compared to IC50 = 79 nM for AMPA). No affinity for NMDA receptors (NMDA-sensitive [3H]glutamic acid binding) was found, and only weak affinity in [3H]kainic acid binding (IC50 = 6.3 microM) was detected. The excitatory activity in rat cortical wedge also showed that ACPA was more potent than AMPA (EC50 = 1.0 microM compared to EC50 = 3.5 microM for AMPA). The depolarizing effect of ACPA could be fully antagonized by the selective non-NMDA antagonist 6-cyano-7-nitro-quinoxazoline-2,3-dione (CNQX), but was unaffected by the selective NMDA antagonist D-2-amino-5-phosphonovaleric acid (AP5).
|
Compound tested for binding affinity towards Ionotropic glutamate receptor kainate
|
None
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : Ibotenic acid analogues. Synthesis and biological and in vitro activity of conformationally restricted agonists at central excitatory amino acid receptors.
Year : 1984
Volume : 27
Issue : 5
First Page : 585
Last Page : 591
Authors : Krogsgaard-Larsen P, Nielsen EO, Curtis DR.
Abstract : A number of analogues of ibotenic acid [(RS)-3-hydroxy-5- isoxazoleglycine ] were synthesized; they were tested as excitants on neurons in the cat spinal cord, by using microelectrophoretic techniques, and as inhibitors of the binding of kainic acid (KA) in vitro, by using synaptic membranes prepared from rat brains. The excitatory effects of the 3- isoxazolol amino acids (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5, 4-c]pyridine-7-carboxylic acid (4, 7- HPCA ), (RS)-alpha-amino-3-hydroxy-5,6-dihydro-4H- cyclohept [1,2-d] isoxa zole - 8-propionic acid (8, 8- AHCP ), (RS)-alpha-amino-3- hydroxy-7,8-dihydro-6H- cyclohept [1,2-d] isoxazole -4-propionic acid (12, 4- AHCP ), and (RS)-alpha-(methylamino)-3-hydroxy-5-methyl- 4- isoxazolepropionic acid (15, N-Me-AMPA) were shown to be sensitive to (S)-glutamic acid diethyl ester (GDEE), an antagonist at quisqualic acid ( QUIS ) receptors, and insensitive to (RS)-2-amino-5-phosphonovaleric acid ( 2APV ), an antagonist at N-methyl-(R)-aspartic acid (NMDA) receptors. The compounds 4 and 12 proved to be particularly potent agonists at the former class of receptor, assumed to represent physiological glutamic acid receptors. The amino acids (RS)-beta-(2-carboxyphenyl)alanine (19), an analogue of 12, and (RS)-2-(3-carboxyphenyl) glycine were weak GDEE-sensitive excitants with potencies comparable with that of 8. All of the compounds were tested as inhibitors of KA binding. With the exception of 12 and 19, which showed very low affinity for the KA binding sites, the compounds studied were inactive in this in vitro test system.
|
Compound was evaluated for the inhibition of [3H]-KA binding to Ionotropic glutamate receptor kainate from rat brain synaptic membrane.
|
None
|
120.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses of trans-3-substituted-CCG-IV analogs and their characterization to ionotropic glutamate receptors
Year : 1996
Volume : 6
Issue : 20
First Page : 2381
Last Page : 2386
Authors : Shimamoto K, Shigeri Y, Nakajima T, Yumoto N, Yoshikawa S, Ohfune Y
|
Inhibition of specific binding of [3H]kainate to Ionotropic glutamate receptor kainate in rat brain membranes
|
None
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure--activity studies for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid receptors: acidic hydroxyphenylalanines.
Year : 1997
Volume : 40
Issue : 20
First Page : 3182
Last Page : 3191
Authors : Hill RA, Wallace LJ, Miller DD, Weinstein DM, Shams G, Tai H, Layer RT, Willins D, Uretsky NJ, Danthi SN.
Abstract : Antagonists of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptors may have therapeutic potential as psychotropic agents. A series of mononitro- and dinitro-2- and 3-hydroxyphenylalanines was prepared, and their activity compared with willardiine, 5-nitrowillardiine, AMPA, and 2,4,5-trihydroxyphenylalanine (6-hydroxydopa) as inhibitors of specific [3H]AMPA and [3H]kainate binding in rat brain homogenates. The most active compounds were highly acidic (pKa 3-4), namely, 2-hydroxy-3,5-dinitro-DL-phenylalanine (13; [3H]AMPA IC50 approximately equal to 25 microM) and 3-hydroxy-2,4-dinitro-DL-phenylalanine (19; [3H]AMPA IC50 approximately equal to 5 microM). Two other dinitro-3-hydroxyphenylalanines, and 3,5-dinitro-DL-tyrosine, were considerably less active. Various mononitrohydroxyphenylalanines, which are less acidic, were also less active or inactive, and 2- and 3-hydroxyphenylalanine (o- and m-tyrosine) were inactive. Compounds 13 and 19, DL-willardiine (pKa 9.3, [3H]AMPA IC50 = 2 microM), and 5-nitro-DL-willardiine (pKa 6.4, [3H]AMPA IC50 = 0.2 microM) displayed AMPA >> kainate selectivity in binding studies. Compound 19 was an AMPA-like agonist, but 13 was an antagonist in an AMPA-evoked norepinephrine release assay in rat hippocampal nerve endings. Also, compound 13 injected into the rat ventral pallidum antagonized the locomotor activity elicited by systemic amphetamine.
|
Binding affinity towards Ionotropic glutamate receptor kainate by displacement of [3H]-kainic acid radioligand
|
None
|
63.0
nM
|
|
Journal : J. Med. Chem.
Title : A rational approach to the design of selective substrates and potent nontransportable inhibitors of the excitatory amino acid transporter EAAC1 (EAAT3). new glutamate and aspartate analogues as potential neuroprotective agents.
Year : 2001
Volume : 44
Issue : 16
First Page : 2507
Last Page : 2510
Authors : Campiani G, De Angelis M, Armaroli S, Fattorusso C, Catalanotti B, Ramunno A, Nacci V, Novellino E, Grewer C, Ionescu D, Rauen T, Griffiths R, Sinclair C, Fumagalli E, Mennini T.
|
Concentration for half maximal activation of metabotropic glutamate mGluR8 in mouse
|
None
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : Metabotropic glutamate receptors: novel targets for drug development.
Year : 1995
Volume : 38
Issue : 9
First Page : 1417
Last Page : 1426
Authors : Knöpfel T, Kuhn R, Allgeier H.
|
Inhibition of binding to rat mGluR1a (metabotropic glutamate receptor) expressed in HEK-293 cells
|
Rattus norvegicus
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : Common and selective molecular determinants involved in metabotopic glutamate receptor agonist activity.
Year : 2002
Volume : 45
Issue : 15
First Page : 3171
Last Page : 3183
Authors : Bertrand HO, Bessis AS, Pin JP, Acher FC.
Abstract : Several potent and group selective agonists of metabotropic glutamate receptors (mGluRs) have been docked at mGlu1,2,4R binding sites in the closed conformation of the bilobate extracellular domain. Quisqualic acid and (S)-3,5-dihydroxyphenylglycine (3,5-DHPG) were selected for mGlu1R, dicarboxycyclopropylglycine (DCG-IV), LY354740, (S)-4-carboxyphenylglycine (4CPG) for mGlu2R, and (S)-2-amino-4-phosphonobutyric acid (AP4), 1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I), (S)-4-phosphonophenylglycine (PPG) for mGlu4R. The models show a conserved binding pattern for the glycine moiety (alpha-amino and alpha-acidic functions) and group specific bindings for the distal acidic function. The best agonists allow optimized interaction with both lobes of the binding domain. Interlobe connections around the ligand are also described and participate in stabilizing the closed form of the amino-terminal domain. Altogether, the docking models support the proposal that the stabilization of a closed state represents a key step in agonist activation of mGluRs.
|
Compound was tested for the inhibition of metabotropic glutamate receptor 2 (mGluR2).
|
None
|
290.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biology of the conformationally restricted ACPD analogue, 2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic acid-I, a potent mGluR agonist.
Year : 1998
Volume : 41
Issue : 10
First Page : 1641
Last Page : 1650
Authors : Kozikowski AP, Steensma D, Araldi GL, Tückmantel W, Wang S, Pshenichkin S, Surina E, Wroblewski JT.
Abstract : To better characterize the roles of metabotropic glutamate receptors (mGluRs) in physiological and pathophysiological processes, there is an important need to learn more about the structural features relevant to the design of novel, high-affinity ligands that are family and subtype specific. To date, many of the biological studies that have been conducted in the area of mGluR research have made use of the agonist (1S,3R)-ACPD. This compound has been shown to act as an agonist at both the group I and group II receptors while showing little selectivity among the four subtypes belonging to these two groups. Moreover, (1S,3S)-ACPD, the cis isomer, shows negligible activity at group I receptors and is a good agonist of mGluR2. Since ACPD is itself somewhat flexible, with four distinctive conformations being identified from molecular modeling studies for the trans isomer and five conformations for the cis isomer, we believed that it would be of interest to examine the activity of an ACPD analogue that has been constrained through the introduction of a single carbon atom bridge. Accordingly, we have prepared an aminobicyclo[2.1.1]hexanedicarboxylic acid (ABHxD-I) analogue of ACPD. The synthesis of this compound was accomplished by use of an intramolecular [2 + 2] photocycloaddition reaction, in which four distinct isomers were isolated. Of these four compounds, only a single isomer, ABHxD-I (6a), was found to be a potent agonist of the mGluRs. This compound, which expresses the fully extended glutamate conformation, was found to be more potent than ACPD at all six of the eight mGluR subtypes that were investigated and to be comparable to or more potent than the endogenous ligand, glutamate, for these receptors. Interestingly, despite its fixed conformation, ABHxD-I, like glutamate, shows little subtype selectivity. Through modeling studies of ABHxD-I (6a), ABHD-VI, LY354740, (1S,3R)-ACPD, (1S, 3S)-ACPD, and l-glutamate, we conclude that the aa conformation of l-glutamate is the active conformation for both group I and group II mGluRs. Moreover, the modeling-based comparisons of these ligands suggest that the selectivity exhibited by LY354740 between the group I and group II mGluRs is not a consequence of different conformations of L-glutamate being required for recognition at these mGluRs but rather is related to certain structural elements within certain regions having a very different impact on the group I and group II mGluR activity. The enhanced potency of ABHxD-I relative to trans-ACPD commends it as a useful starting point in the design of subtype selective mGluR ligands.
|
Binding affinity was measured by NMDA sensitive [3H]- glutamic acid receptor binding assay.
|
None
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Heterocyclic excitatory amino acids. Synthesis and biological activity of novel analogues of AMPA.
Year : 1992
Volume : 35
Issue : 1
First Page : 107
Last Page : 111
Authors : Madsen U, Wong EH.
Abstract : The novel acidic amino acids 6a-c, 7, and 8 have been synthesized via 1,3-dipolar cycloadditions, using nitrile oxides and alkynes. The prepared compounds are heterocyclic analogues of glutamic acid with differing chain lengths. One of these compounds, (RS)-2-amino-3-(3-carboxy-5-methyl-4- isoxazolyl)propionic acid (ACPA, 8), was shown in [3H]AMPA binding studies to be more active than AMPA itself (IC50 = 20 nM compared to IC50 = 79 nM for AMPA). No affinity for NMDA receptors (NMDA-sensitive [3H]glutamic acid binding) was found, and only weak affinity in [3H]kainic acid binding (IC50 = 6.3 microM) was detected. The excitatory activity in rat cortical wedge also showed that ACPA was more potent than AMPA (EC50 = 1.0 microM compared to EC50 = 3.5 microM for AMPA). The depolarizing effect of ACPA could be fully antagonized by the selective non-NMDA antagonist 6-cyano-7-nitro-quinoxazoline-2,3-dione (CNQX), but was unaffected by the selective NMDA antagonist D-2-amino-5-phosphonovaleric acid (AP5).
|
Compound was evaluated for the inhibition of [3H]MK-801 binding at N-methyl-D-aspartate glutamate receptor
|
None
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : DL-tetrazol-5-ylglycine, a highly potent NMDA agonist: its synthesis and NMDA receptor efficacy.
Year : 1992
Volume : 35
Issue : 24
First Page : 4608
Last Page : 4612
Authors : Lunn WH, Schoepp DD, Calligaro DO, Vasileff RT, Heinz LJ, Salhoff CR, O'Malley PJ.
Abstract : At physiological pH, the spatial arrangement of the three charges of DL-tetrazol-5-ylglycine (5) could be viewed as similar to those found in certain conformations of the two excitatory amino acids (EAAs)--aspartic and glutamic acids. Given significant binding to one or more EAA receptors, 5 would offer unique modeling and perhaps biological opportunities. We have previously shown it to be the most potent NMDA agonist known, with a unique and marked in vitro neutrotoxicity at depolarizing concentrations. Now we report the details required for its synthesis, together with its potency and efficacy in two assays of functional activation of the NMDA receptor, namely agonist-influenced [3H]MK801 binding and agonist-induced release of the neurotransmitter [3H]-norepinephrine from brain slices. In both these assays DL-tetrazol-5-ylglycine proved to be more potent and efficacious than NMDA and cis-methanoglutamate. It was more potent than, and equally efficacious to, L-glutamate in [3H]MK801 binding. The structural features of 5 may well reflect optimal agonist interaction at the NMDA receptor site. (We considered the possibility that some decarboxylation of DL-tetrazol-5-ylglycine may have occurred during testing. This would give 5-(aminomethyl)tetrazole (13), the tetrazole acid analog of glycine; and glycine is involved in NMDA receptor activation. Compound 13 does not affect [3H]glycine binding at the strychnine-insensitive glycine binding site, and [3H]MK801 binding studies showed that the (aminomethyl)-tetrazole, even if is formed, would probably have no effect on the activity of tetrazol-5-ylglycine at the NMDA receptor.
|
Compound was evaluated for the inhibition of [3H]-CGS-19,755 binding at N-methyl-D-aspartate glutamate receptor
|
None
|
172.0
nM
|
|
Journal : J. Med. Chem.
Title : DL-tetrazol-5-ylglycine, a highly potent NMDA agonist: its synthesis and NMDA receptor efficacy.
Year : 1992
Volume : 35
Issue : 24
First Page : 4608
Last Page : 4612
Authors : Lunn WH, Schoepp DD, Calligaro DO, Vasileff RT, Heinz LJ, Salhoff CR, O'Malley PJ.
Abstract : At physiological pH, the spatial arrangement of the three charges of DL-tetrazol-5-ylglycine (5) could be viewed as similar to those found in certain conformations of the two excitatory amino acids (EAAs)--aspartic and glutamic acids. Given significant binding to one or more EAA receptors, 5 would offer unique modeling and perhaps biological opportunities. We have previously shown it to be the most potent NMDA agonist known, with a unique and marked in vitro neutrotoxicity at depolarizing concentrations. Now we report the details required for its synthesis, together with its potency and efficacy in two assays of functional activation of the NMDA receptor, namely agonist-influenced [3H]MK801 binding and agonist-induced release of the neurotransmitter [3H]-norepinephrine from brain slices. In both these assays DL-tetrazol-5-ylglycine proved to be more potent and efficacious than NMDA and cis-methanoglutamate. It was more potent than, and equally efficacious to, L-glutamate in [3H]MK801 binding. The structural features of 5 may well reflect optimal agonist interaction at the NMDA receptor site. (We considered the possibility that some decarboxylation of DL-tetrazol-5-ylglycine may have occurred during testing. This would give 5-(aminomethyl)tetrazole (13), the tetrazole acid analog of glycine; and glycine is involved in NMDA receptor activation. Compound 13 does not affect [3H]glycine binding at the strychnine-insensitive glycine binding site, and [3H]MK801 binding studies showed that the (aminomethyl)-tetrazole, even if is formed, would probably have no effect on the activity of tetrazol-5-ylglycine at the NMDA receptor.
|
Inhibition of N-methyl-D-aspartate glutamate receptor by using [3H]CPP as a radioligand from the rat cortical membranes.
|
None
|
171.0
nM
|
|
Journal : J. Med. Chem.
Title : New and versatile approaches to the synthesis of CPP-related competitive NMDA antagonists. Preliminary structure-activity relationships and pharmacological evaluation.
Year : 1990
Volume : 33
Issue : 10
First Page : 2916
Last Page : 2924
Authors : Hays SJ, Bigge CF, Novak PM, Drummond JT, Bobovski TP, Rice MJ, Johnson G, Brahce LJ, Coughenour LL.
Abstract : Fourteen new CPP analogues have been prepared with methyl 1-(phenylmethyl) (+/-)-1,2-piperazinedicarboxylate 3 as a versatile synthetic intermediate. Derivatives were evaluated as NMDA ligands by their ability to displace [3H]CPP from rat cortical membranes. The binding affinity of various chain lengths at the N4-position of the CPP analogues, 5a, 5b, and 9a mimics the binding affinity observed for the acyclic derivatives AP6, AP8, and AP5. Analogue 9a, with a single methylene group in its phosphonate side chain, exhibited diminished affinity for the NMDA receptor when compared to the structurally similar piperidine compound CGS 19755. Replacement of the phosphonic acid moiety with monoionizable acidic groups such as a carboxylate or a phosphinate resulted in a reduction of binding affinity. An aryl spacer between the N4-nitrogen and the distal acidic group was detrimental to binding as was alkylation at the N1-position. Steric bulk, however, was better tolerated when a phenyl group was positioned alpha to the phosphonate, as seen with analogues 21 and 22.
|
Compound was evaluated for the inhibition of [3H]CGS-19,755 binding to NMDA receptor from rat brain synaptic membrane.
|
None
|
80.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses of trans-3-substituted-CCG-IV analogs and their characterization to ionotropic glutamate receptors
Year : 1996
Volume : 6
Issue : 20
First Page : 2381
Last Page : 2386
Authors : Shimamoto K, Shigeri Y, Nakajima T, Yumoto N, Yoshikawa S, Ohfune Y
|
Inhibition of [3H]CPP binding to rat N-methyl-D-aspartate glutamate receptor
|
Rattus norvegicus
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : Bioisosteric replacement of the alpha-amino carboxylic acid functionality in 2-amino-5-phosphonopentanoic acid yields unique 3,4-diamino-3-cyclobutene-1,2-dione containing NMDA antagonists.
Year : 1992
Volume : 35
Issue : 25
First Page : 4720
Last Page : 4726
Authors : Kinney WA, Lee NE, Garrison DT, Podlesny EJ, Simmonds JT, Bramlett D, Notvest RR, Kowal DM, Tasse RP.
Abstract : In this report, a novel bioisostere of the alpha-amino acid, 3,4-diamino-3-cyclobutene-1,2-dione, has been incorporated into a series of compounds which are NMDA antagonists. These compounds, which are achiral and easily prepared, demonstrated good affinity at the NMDA receptor by their ability to displace [3H]CPP binding in vitro. In particular, the phosphonic acid 24 provided protection against NMDA-induced lethality in mice equivalent to 2-amino-7-phosphonoheptanoic acid (5). This was considered an encouraging result in lieu of the fact that 24, like 5, lacks the conformational rigidity of the more potent NMDA antagonists. In addition, analogs that incorporate the 1,2,4-oxadiazolidine-3,5-dione heterocycle of quisqualic acid and the unsaturation of kainic acid were prepared to explore selectivity at the non-NMDA receptor subtypes.
|
Binding affinity towards NMDA receptor by displacement of [3H]CGP-39653 radioligand.
|
None
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : A rational approach to the design of selective substrates and potent nontransportable inhibitors of the excitatory amino acid transporter EAAC1 (EAAT3). new glutamate and aspartate analogues as potential neuroprotective agents.
Year : 2001
Volume : 44
Issue : 16
First Page : 2507
Last Page : 2510
Authors : Campiani G, De Angelis M, Armaroli S, Fattorusso C, Catalanotti B, Ramunno A, Nacci V, Novellino E, Grewer C, Ionescu D, Rauen T, Griffiths R, Sinclair C, Fumagalli E, Mennini T.
|
Effective concentration against NR1/NR2B receptor
|
None
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : Ligands for glutamate receptors: design and therapeutic prospects.
Year : 2000
Volume : 43
Issue : 14
First Page : 2609
Last Page : 2645
Authors : Bräuner-Osborne H, Egebjerg J, Nielsen EO, Madsen U, Krogsgaard-Larsen P.
|
Effective concentration against NR1/NR2C receptor
|
None
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Ligands for glutamate receptors: design and therapeutic prospects.
Year : 2000
Volume : 43
Issue : 14
First Page : 2609
Last Page : 2645
Authors : Bräuner-Osborne H, Egebjerg J, Nielsen EO, Madsen U, Krogsgaard-Larsen P.
|
Effective concentration against NR1/NR2D receptor
|
None
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : Ligands for glutamate receptors: design and therapeutic prospects.
Year : 2000
Volume : 43
Issue : 14
First Page : 2609
Last Page : 2645
Authors : Bräuner-Osborne H, Egebjerg J, Nielsen EO, Madsen U, Krogsgaard-Larsen P.
|
In vitro binding affinity against synaptic membrane from rat brain using [3H]-AMPA as the radioligand
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Excitatory amino acid agonists. Enzymic resolution, X-ray structure, and enantioselective activities of (R)- and (S)-bromohomoibotenic acid.
Year : 1989
Volume : 32
Issue : 10
First Page : 2254
Last Page : 2260
Authors : Hansen JJ, Nielsen B, Krogsgaard-Larsen P, Brehm L, Nielsen EO, Curtis DR.
Abstract : The enantiomers of alpha-amino-4-bromo-3-hydroxy-5-isoxazolepropionic acid (4-bromohomoibotenic acid, Br-HIBO, 1) a selective and potent agonist at one class of the central (S)-glutamic acid receptors, were prepared with an enantiomeric excess higher than 98.8% via stereoselective enzymic hydrolysis of (RS)-alpha-(acetylamino)-4-bromo-3-methoxy-5-isoxazolepropionic acid (4) using immobilized aminoacylase. The absolute configuration of the enantiomers of Br-HIBO was established by X-ray crystallographic analysis, which confirmed the expected preference of the enzyme for the S form of the substrate 4. (S)- and (RS)-Br-HIBO were potent neuroexcitants on cat spinal neurones in vivo, while (R)-Br-HIBO was a very weak excitant. Correspondingly, the S enantiomer of Br-HIBO (IC50 = 0.34 microM) was considerably more potent than the R form (IC50 = 32 microM) as an inhibitor of [3H]-(RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([ 3H]AMPA) binding to rat brain synaptic membranes in vitro. In contrast, (S)- and (R)-Br-HIBO were approximately equipotent (IC50 values of 0.22 and 0.15 microM, respectively) as inhibitors of [3H]-(S)-glutamic acid binding in the presence of CaCl2. The enantiomers of Br-HIBO showed no significant affinity for those binding sites on rat brain membranes which are labeled by [3H]kainic acid or [3H]-(R)-aspartic acid.
|
In vitro binding affinity against synaptic membrane from rat brain using [3H]KAIN as the radioligand
|
None
|
270.0
nM
|
|
Journal : J. Med. Chem.
Title : Excitatory amino acid agonists. Enzymic resolution, X-ray structure, and enantioselective activities of (R)- and (S)-bromohomoibotenic acid.
Year : 1989
Volume : 32
Issue : 10
First Page : 2254
Last Page : 2260
Authors : Hansen JJ, Nielsen B, Krogsgaard-Larsen P, Brehm L, Nielsen EO, Curtis DR.
Abstract : The enantiomers of alpha-amino-4-bromo-3-hydroxy-5-isoxazolepropionic acid (4-bromohomoibotenic acid, Br-HIBO, 1) a selective and potent agonist at one class of the central (S)-glutamic acid receptors, were prepared with an enantiomeric excess higher than 98.8% via stereoselective enzymic hydrolysis of (RS)-alpha-(acetylamino)-4-bromo-3-methoxy-5-isoxazolepropionic acid (4) using immobilized aminoacylase. The absolute configuration of the enantiomers of Br-HIBO was established by X-ray crystallographic analysis, which confirmed the expected preference of the enzyme for the S form of the substrate 4. (S)- and (RS)-Br-HIBO were potent neuroexcitants on cat spinal neurones in vivo, while (R)-Br-HIBO was a very weak excitant. Correspondingly, the S enantiomer of Br-HIBO (IC50 = 0.34 microM) was considerably more potent than the R form (IC50 = 32 microM) as an inhibitor of [3H]-(RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([ 3H]AMPA) binding to rat brain synaptic membranes in vitro. In contrast, (S)- and (R)-Br-HIBO were approximately equipotent (IC50 values of 0.22 and 0.15 microM, respectively) as inhibitors of [3H]-(S)-glutamic acid binding in the presence of CaCl2. The enantiomers of Br-HIBO showed no significant affinity for those binding sites on rat brain membranes which are labeled by [3H]kainic acid or [3H]-(R)-aspartic acid.
|
In vitro binding affinity against synaptic membrane from rat brain using [3H](S)-Glu as the radioligand
|
Rattus norvegicus
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : Excitatory amino acid agonists. Enzymic resolution, X-ray structure, and enantioselective activities of (R)- and (S)-bromohomoibotenic acid.
Year : 1989
Volume : 32
Issue : 10
First Page : 2254
Last Page : 2260
Authors : Hansen JJ, Nielsen B, Krogsgaard-Larsen P, Brehm L, Nielsen EO, Curtis DR.
Abstract : The enantiomers of alpha-amino-4-bromo-3-hydroxy-5-isoxazolepropionic acid (4-bromohomoibotenic acid, Br-HIBO, 1) a selective and potent agonist at one class of the central (S)-glutamic acid receptors, were prepared with an enantiomeric excess higher than 98.8% via stereoselective enzymic hydrolysis of (RS)-alpha-(acetylamino)-4-bromo-3-methoxy-5-isoxazolepropionic acid (4) using immobilized aminoacylase. The absolute configuration of the enantiomers of Br-HIBO was established by X-ray crystallographic analysis, which confirmed the expected preference of the enzyme for the S form of the substrate 4. (S)- and (RS)-Br-HIBO were potent neuroexcitants on cat spinal neurones in vivo, while (R)-Br-HIBO was a very weak excitant. Correspondingly, the S enantiomer of Br-HIBO (IC50 = 0.34 microM) was considerably more potent than the R form (IC50 = 32 microM) as an inhibitor of [3H]-(RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([ 3H]AMPA) binding to rat brain synaptic membranes in vitro. In contrast, (S)- and (R)-Br-HIBO were approximately equipotent (IC50 values of 0.22 and 0.15 microM, respectively) as inhibitors of [3H]-(S)-glutamic acid binding in the presence of CaCl2. The enantiomers of Br-HIBO showed no significant affinity for those binding sites on rat brain membranes which are labeled by [3H]kainic acid or [3H]-(R)-aspartic acid.
|
Inhibitory activity against Tetanus neurotoxin (TeNt) light chain by using fluorescent synaptobrevin derivative [Pya88]S 39-88 as substrate at 10e-3 M.
|
None
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Beta-amino-thiols inhibit the zinc metallopeptidase activity of tetanus toxin light chain.
Year : 1998
Volume : 41
Issue : 18
First Page : 3450
Last Page : 3460
Authors : Martin L, Cornille F, Coric P, Roques BP, Fournié-Zaluski MC.
Abstract : Tetanus neurotoxin is a 150-kDa protein produced by Clostridium tetani, which causes the lethal spastic paralytic syndromes of tetanus by blocking inhibitory neurotransmitter release at central synapses. The toxin light chain (50 kDa) has a zinc endopeptidase activity specific for synaptobrevin, an essential component of the neuroexocytosis apparatus. Previous unsuccessful attempts to block the proteolytic activity of this neurotoxin with well-known inhibitors of other zinc proteases led us to study the design of specific inhibitors as a possible drug therapy to prevent the progressive evolution of tetanus following infection. Starting from the synaptobrevin sequence at the level of the cleavage site by tetanus neurotoxin (Gln76-Phe77), a thiol analogue of glutamine demonstrated inhibitory activities in the millimolar range. A structure-activity relationship performed with this compound led us to determine the requirement for the correct positioning of the thiol group, the primary amino group, and a carboxamide or sulfonamide group on the side chain. This resulted in the design of a beta-amino-(4-sulfamoylphenyl)glycine-thiol, the first significantly efficient inhibitor of tetanus neurotoxin with a Ki value of 35 +/- 5 microM.
|
Agonistic activity evaluated in CHO(Chinese hamster ovary) cells expressing mGluR2 receptor
|
None
|
610.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-amino-APDC, a partial agonist of group II metabotropic glutamate receptors with neuroprotective properties.
Year : 1999
Volume : 9
Issue : 12
First Page : 1721
Last Page : 1726
Authors : Kozikowski AP, Araldi GL, Tückmantel W, Pshenichkin S, Surina E, Wroblewski JT.
Abstract : The synthesis of the 1-amino derivative of (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylic acid (1-amino-APDC), a selective metabotropic glutamate ligand, is disclosed. This compound acts as a partial agonist of the group II mGluRs and shows pronounced neuroprotective properties in the NMDA model of cell toxicity.
|
Displacement of L-[3H]glutamate from N-methyl-D-aspartate glutamate receptor in rat brain synaptic membranes
|
Rattus norvegicus
|
870.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Analogues of the neuroprotective tripeptide Gly-Pro-Glu (GPE): synthesis and structure-activity relationships.
Year : 2005
Volume : 15
Issue : 9
First Page : 2279
Last Page : 2283
Authors : Alonso De Diego SA, Muñoz P, González-Muñiz R, Herranz R, Martín-Martínez M, Cenarruzabeitia E, Frechilla D, Del Río J, Jimeno ML, García-López MT.
Abstract : A series of GPE analogues, including modifications at the Pro and/or Glu residues, was prepared and evaluated for their NMDA binding and neuroprotective effects. Main results suggest that the pyrrolidine ring puckering of the Pro residue plays a key role in the biological responses, while the preference for cis or trans rotamers around the Gly-Pro peptide bond is not important.
|
Inhibitory concentration against [3H]1 binding to recombinant human Metabotropic glutamate receptor 8
|
Homo sapiens
|
5.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (2S,1'S,2'R,3'R)-2(2'-Carboxy-3'-hydroxymethylcyclopropyl)glycine-[3H], a potent and selective radioligand for labeling group 2 and 3 metabotropic glutamate receptors.
Year : 2005
Volume : 15
Issue : 2
First Page : 349
Last Page : 351
Authors : Wheeler WJ, Clodfelter DK, Collado I, Kulanthaivel P, Pedregal C, Stoddard EA, Wright RA, Schoepp DD.
Abstract : We report herein the synthesis of the tritium labeled isotopomer of 1 and its use as a radioligand to label mGlu8 receptors in rat forebrain membranes as well as cloned human recombinant mGlu receptors. [(3)H]-1 was synthesized by the NaBT(4) reduction of an activated analog of 5. [(3)H]-1 bound appreciably to recombinant human mGlu2, mGlu3 and mGlu8 receptors and to rat forebrain membranes and was displaced by L-glutamate and L-(+)-2 amino-4-phosphonobutyric acid. The results indicate that [(3)H]-1 should be a useful ligand for the study of mGluR2, 3, and 8 receptors in cloned cell lines and possibly brain tissue.
|
Percent inhibition against AMPA receptor at 1 uM
|
Homo sapiens
|
613.0
nM
|
|
Journal : J. Med. Chem.
Title : 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine and analogues as A2A adenosine receptor antagonists. Design, synthesis, and pharmacological characterization.
Year : 2005
Volume : 48
Issue : 22
First Page : 6887
Last Page : 6896
Authors : Minetti P, Tinti MO, Carminati P, Castorina M, Di Cesare MA, Di Serio S, Gallo G, Ghirardi O, Giorgi F, Giorgi L, Piersanti G, Bartoccini F, Tarzia G.
Abstract : Two types of adenosine receptor ligands were designed, i.e., 9H-purine and 1H-imidazo[4,5-c]pyridines, to obtain selective A(2A) antagonists, and we report here their synthesis and binding affinities for the four adenosine receptor subtypes A(1), A(2A), A(2B) and A(3). The design was carried out on the basis of the molecular modeling of a number of potent adenosine receptor antagonists described in the literature. Three compounds (25b-d) showed an interesting affinity and selectivity for the A(2A) subtype. One of them, i.e., ST1535 (2-n-butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine, 25b) (K(i) A(2A) = 6.6 nM, K(i) A(1)/A(2A) = 12; K(i) A(2B)/A(2A) = 58; K(i) A(3)/A(2A) > 160), was selected for in vivo study and shown to induce a dose-related increase in locomotor activity, suggestive of an A(2A) antagonist type of activity.
|
Antagonist activity against AMPA receptor expressed in motoneurones by inhibition of fDR-VRP in the neonatal rat spinal cord
|
Rattus norvegicus
|
214.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship studies on N3-substituted willardiine derivatives acting as AMPA or kainate receptor antagonists.
Year : 2006
Volume : 49
Issue : 8
First Page : 2579
Last Page : 2592
Authors : Dolman NP, More JC, Alt A, Knauss JL, Troop HM, Bleakman D, Collingridge GL, Jane DE.
Abstract : N3-substitution of the uracil ring of willardiine with a variety of carboxyalkyl or carboxybenzyl substituents produces AMPA and kainate receptor antagonists. In an attempt to improve the potency and selectivity of these AMPA and kainate receptor antagonists a series of analogues with different terminal acidic groups and interacidic group spacers was synthesized and pharmacologically characterized. (S)-1-(2-Amino-2-carboxyethyl)-3-(2-carboxythiophene-3-ylmethyl)pyrimidine-2,4-dione (43, UBP304) demonstrated high potency and selectivity toward native GLU(K5)-containing kainate receptors (K(D) 0.105 +/- 0.007 microM vs kainate on native GLU(K5); K(D) 71.4 +/- 8.3 microM vs (S)-5-fluorowillardiine on native AMPA receptors). On recombinant human GLU(K5), GLU(K5)/GLU(K6), and GLU(K5)/GLU(K2), K(B) values of 0.12 +/- 0.03, 0.12 +/- 0.01, and 0.18 +/- 0.02 microM, respectively, were obtained for 43. However, 43 displayed no activity on homomeric GLU(K6) or GLU(K7) kainate receptors or homomeric GLU(A1-4) AMPA receptors (IC(50) values > 100 microM). Thus, 43 is a potent and selective GLU(K5) receptor antagonist.
|
Displacement of [3H]quisqualate from mGluR1 receptor expressed in BHK cells
|
Homo sapiens
|
250.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, molecular modeling studies, and preliminary pharmacological characterization of all possible 2-(2'-sulfonocyclopropyl)glycine stereoisomers as conformationally constrained L-homocysteic acid analogs.
Year : 2007
Volume : 50
Issue : 19
First Page : 4630
Last Page : 4641
Authors : Pellicciari R, Marinozzi M, Macchiarulo A, Fulco MC, Gafarova J, Serpi M, Giorgi G, Nielsen S, Thomsen C.
Abstract : Bioisosteric replacements of the distal acidic group of L-glutamic acid (L-Glu, 1) and conformational constraining of its carbon skeleton, have been widely exploited to discover competitive modulators of glutamate receptors. Noteworthy, L-homocysteic acid (L-HCA, 18), a neurotransmitter belonging to the class of excitatory sulfur-containing amino acids, may be considered an endogenous occurring bioisoster of L-Glu (1). L-HCA (18) has been reported to mediate signaling between glial cells and postsynaptic neurons through the activation of glutamate receptors and others hitherto not well-characterized receptors. As a continuation of our work in the preparation of conformationally constrained glutamate analogs, we report the synthesis and the preliminary pharmacological characterization at iGluRs and mGluRs of all eight stereoisomers of 2-(2'-sulfonocyclopropyl)glycine (SCGs, 8-15). Among the reported compounds, S-SCG-4 (15) showed to be a potent and relatively selective AMPA ligand. Docking experiments coupled to molecular electrostatic potential calculations allowed insight into the molecular basis of the activity of this compound to be gained. The library of SCGs (8-15), while providing a novel source of modulators of the glutamate receptors, represents a valuable chemical tool to better characterize L-HCA pathways in the CNS.
|
Binding affinity to mGluR5 receptor expressed in BHK cells
|
Homo sapiens
|
390.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, molecular modeling studies, and preliminary pharmacological characterization of all possible 2-(2'-sulfonocyclopropyl)glycine stereoisomers as conformationally constrained L-homocysteic acid analogs.
Year : 2007
Volume : 50
Issue : 19
First Page : 4630
Last Page : 4641
Authors : Pellicciari R, Marinozzi M, Macchiarulo A, Fulco MC, Gafarova J, Serpi M, Giorgi G, Nielsen S, Thomsen C.
Abstract : Bioisosteric replacements of the distal acidic group of L-glutamic acid (L-Glu, 1) and conformational constraining of its carbon skeleton, have been widely exploited to discover competitive modulators of glutamate receptors. Noteworthy, L-homocysteic acid (L-HCA, 18), a neurotransmitter belonging to the class of excitatory sulfur-containing amino acids, may be considered an endogenous occurring bioisoster of L-Glu (1). L-HCA (18) has been reported to mediate signaling between glial cells and postsynaptic neurons through the activation of glutamate receptors and others hitherto not well-characterized receptors. As a continuation of our work in the preparation of conformationally constrained glutamate analogs, we report the synthesis and the preliminary pharmacological characterization at iGluRs and mGluRs of all eight stereoisomers of 2-(2'-sulfonocyclopropyl)glycine (SCGs, 8-15). Among the reported compounds, S-SCG-4 (15) showed to be a potent and relatively selective AMPA ligand. Docking experiments coupled to molecular electrostatic potential calculations allowed insight into the molecular basis of the activity of this compound to be gained. The library of SCGs (8-15), while providing a novel source of modulators of the glutamate receptors, represents a valuable chemical tool to better characterize L-HCA pathways in the CNS.
|
Displacement of [3H]CGP-39653 from rat NMDA receptor expressed in BHK cells
|
Rattus norvegicus
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, molecular modeling studies, and preliminary pharmacological characterization of all possible 2-(2'-sulfonocyclopropyl)glycine stereoisomers as conformationally constrained L-homocysteic acid analogs.
Year : 2007
Volume : 50
Issue : 19
First Page : 4630
Last Page : 4641
Authors : Pellicciari R, Marinozzi M, Macchiarulo A, Fulco MC, Gafarova J, Serpi M, Giorgi G, Nielsen S, Thomsen C.
Abstract : Bioisosteric replacements of the distal acidic group of L-glutamic acid (L-Glu, 1) and conformational constraining of its carbon skeleton, have been widely exploited to discover competitive modulators of glutamate receptors. Noteworthy, L-homocysteic acid (L-HCA, 18), a neurotransmitter belonging to the class of excitatory sulfur-containing amino acids, may be considered an endogenous occurring bioisoster of L-Glu (1). L-HCA (18) has been reported to mediate signaling between glial cells and postsynaptic neurons through the activation of glutamate receptors and others hitherto not well-characterized receptors. As a continuation of our work in the preparation of conformationally constrained glutamate analogs, we report the synthesis and the preliminary pharmacological characterization at iGluRs and mGluRs of all eight stereoisomers of 2-(2'-sulfonocyclopropyl)glycine (SCGs, 8-15). Among the reported compounds, S-SCG-4 (15) showed to be a potent and relatively selective AMPA ligand. Docking experiments coupled to molecular electrostatic potential calculations allowed insight into the molecular basis of the activity of this compound to be gained. The library of SCGs (8-15), while providing a novel source of modulators of the glutamate receptors, represents a valuable chemical tool to better characterize L-HCA pathways in the CNS.
|
Displacement of [3H]kainic acid from rat KA receptor expressed in BHK cells
|
Rattus norvegicus
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, molecular modeling studies, and preliminary pharmacological characterization of all possible 2-(2'-sulfonocyclopropyl)glycine stereoisomers as conformationally constrained L-homocysteic acid analogs.
Year : 2007
Volume : 50
Issue : 19
First Page : 4630
Last Page : 4641
Authors : Pellicciari R, Marinozzi M, Macchiarulo A, Fulco MC, Gafarova J, Serpi M, Giorgi G, Nielsen S, Thomsen C.
Abstract : Bioisosteric replacements of the distal acidic group of L-glutamic acid (L-Glu, 1) and conformational constraining of its carbon skeleton, have been widely exploited to discover competitive modulators of glutamate receptors. Noteworthy, L-homocysteic acid (L-HCA, 18), a neurotransmitter belonging to the class of excitatory sulfur-containing amino acids, may be considered an endogenous occurring bioisoster of L-Glu (1). L-HCA (18) has been reported to mediate signaling between glial cells and postsynaptic neurons through the activation of glutamate receptors and others hitherto not well-characterized receptors. As a continuation of our work in the preparation of conformationally constrained glutamate analogs, we report the synthesis and the preliminary pharmacological characterization at iGluRs and mGluRs of all eight stereoisomers of 2-(2'-sulfonocyclopropyl)glycine (SCGs, 8-15). Among the reported compounds, S-SCG-4 (15) showed to be a potent and relatively selective AMPA ligand. Docking experiments coupled to molecular electrostatic potential calculations allowed insight into the molecular basis of the activity of this compound to be gained. The library of SCGs (8-15), while providing a novel source of modulators of the glutamate receptors, represents a valuable chemical tool to better characterize L-HCA pathways in the CNS.
|
Displacement of [3H]AMPA from rat AMPA receptor expressed in BHK cells
|
Rattus norvegicus
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, molecular modeling studies, and preliminary pharmacological characterization of all possible 2-(2'-sulfonocyclopropyl)glycine stereoisomers as conformationally constrained L-homocysteic acid analogs.
Year : 2007
Volume : 50
Issue : 19
First Page : 4630
Last Page : 4641
Authors : Pellicciari R, Marinozzi M, Macchiarulo A, Fulco MC, Gafarova J, Serpi M, Giorgi G, Nielsen S, Thomsen C.
Abstract : Bioisosteric replacements of the distal acidic group of L-glutamic acid (L-Glu, 1) and conformational constraining of its carbon skeleton, have been widely exploited to discover competitive modulators of glutamate receptors. Noteworthy, L-homocysteic acid (L-HCA, 18), a neurotransmitter belonging to the class of excitatory sulfur-containing amino acids, may be considered an endogenous occurring bioisoster of L-Glu (1). L-HCA (18) has been reported to mediate signaling between glial cells and postsynaptic neurons through the activation of glutamate receptors and others hitherto not well-characterized receptors. As a continuation of our work in the preparation of conformationally constrained glutamate analogs, we report the synthesis and the preliminary pharmacological characterization at iGluRs and mGluRs of all eight stereoisomers of 2-(2'-sulfonocyclopropyl)glycine (SCGs, 8-15). Among the reported compounds, S-SCG-4 (15) showed to be a potent and relatively selective AMPA ligand. Docking experiments coupled to molecular electrostatic potential calculations allowed insight into the molecular basis of the activity of this compound to be gained. The library of SCGs (8-15), while providing a novel source of modulators of the glutamate receptors, represents a valuable chemical tool to better characterize L-HCA pathways in the CNS.
|
Displacement of [3H]AMPA from AMPA receptor in rat cortical synaptosome
|
Rattus norvegicus
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands.
Year : 2008
Volume : 51
Issue : 14
First Page : 4179
Last Page : 4187
Authors : Clausen RP, Christensen C, Hansen KB, Greenwood JR, Jørgensen L, Micale N, Madsen JC, Nielsen B, Egebjerg J, Bräuner-Osborne H, Traynelis SF, Kristensen JL.
Abstract : A series of analogues based on N-hydroxypyrazole as a bioisostere for the distal carboxylate group of aspartate have been designed, synthesized, and pharmacologically characterized. Affinity studies on the major glutamate receptor subgroups show that these 4-substituted N-hydroxypyrazol-5-yl glycine (NHP5G) derivatives are selectively recognized by N-methyl- d-aspartic acid (NMDA) receptors and that the ( R)-enantiomers are preferred. Moreover, several of the compounds are able to discriminate between individual subtypes among the NMDA receptors, providing new pharmacological tools. For example, 4-propyl NHP5G is an antagonist at the NR1/NR2A subtype but an agonist at the NR1/NR2D subtype. Molecular docking studies indicate that the substituent protrudes into a region that may be further exploited to improve subtype selectivity, thereby opening up a design strategy for ligands which can differentiate individual NMDA receptor subtypes.
|
Displacement of [3H]KAIN from KA receptor in rat cortical synaptosome
|
Rattus norvegicus
|
380.0
nM
|
|
Journal : J. Med. Chem.
Title : N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands.
Year : 2008
Volume : 51
Issue : 14
First Page : 4179
Last Page : 4187
Authors : Clausen RP, Christensen C, Hansen KB, Greenwood JR, Jørgensen L, Micale N, Madsen JC, Nielsen B, Egebjerg J, Bräuner-Osborne H, Traynelis SF, Kristensen JL.
Abstract : A series of analogues based on N-hydroxypyrazole as a bioisostere for the distal carboxylate group of aspartate have been designed, synthesized, and pharmacologically characterized. Affinity studies on the major glutamate receptor subgroups show that these 4-substituted N-hydroxypyrazol-5-yl glycine (NHP5G) derivatives are selectively recognized by N-methyl- d-aspartic acid (NMDA) receptors and that the ( R)-enantiomers are preferred. Moreover, several of the compounds are able to discriminate between individual subtypes among the NMDA receptors, providing new pharmacological tools. For example, 4-propyl NHP5G is an antagonist at the NR1/NR2A subtype but an agonist at the NR1/NR2D subtype. Molecular docking studies indicate that the substituent protrudes into a region that may be further exploited to improve subtype selectivity, thereby opening up a design strategy for ligands which can differentiate individual NMDA receptor subtypes.
|
Displacement of [3H]CGP39653 from NMDA receptor in rat cortical synaptosome
|
Rattus norvegicus
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands.
Year : 2008
Volume : 51
Issue : 14
First Page : 4179
Last Page : 4187
Authors : Clausen RP, Christensen C, Hansen KB, Greenwood JR, Jørgensen L, Micale N, Madsen JC, Nielsen B, Egebjerg J, Bräuner-Osborne H, Traynelis SF, Kristensen JL.
Abstract : A series of analogues based on N-hydroxypyrazole as a bioisostere for the distal carboxylate group of aspartate have been designed, synthesized, and pharmacologically characterized. Affinity studies on the major glutamate receptor subgroups show that these 4-substituted N-hydroxypyrazol-5-yl glycine (NHP5G) derivatives are selectively recognized by N-methyl- d-aspartic acid (NMDA) receptors and that the ( R)-enantiomers are preferred. Moreover, several of the compounds are able to discriminate between individual subtypes among the NMDA receptors, providing new pharmacological tools. For example, 4-propyl NHP5G is an antagonist at the NR1/NR2A subtype but an agonist at the NR1/NR2D subtype. Molecular docking studies indicate that the substituent protrudes into a region that may be further exploited to improve subtype selectivity, thereby opening up a design strategy for ligands which can differentiate individual NMDA receptor subtypes.
|
Activity at rat NR1/NR2D receptor expressed in Xenopus oocytes assessed as effect on glutamate-induced current by two voltage clamp electrophysiology
|
Rattus norvegicus
|
450.0
nM
|
|
Journal : J. Med. Chem.
Title : N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands.
Year : 2008
Volume : 51
Issue : 14
First Page : 4179
Last Page : 4187
Authors : Clausen RP, Christensen C, Hansen KB, Greenwood JR, Jørgensen L, Micale N, Madsen JC, Nielsen B, Egebjerg J, Bräuner-Osborne H, Traynelis SF, Kristensen JL.
Abstract : A series of analogues based on N-hydroxypyrazole as a bioisostere for the distal carboxylate group of aspartate have been designed, synthesized, and pharmacologically characterized. Affinity studies on the major glutamate receptor subgroups show that these 4-substituted N-hydroxypyrazol-5-yl glycine (NHP5G) derivatives are selectively recognized by N-methyl- d-aspartic acid (NMDA) receptors and that the ( R)-enantiomers are preferred. Moreover, several of the compounds are able to discriminate between individual subtypes among the NMDA receptors, providing new pharmacological tools. For example, 4-propyl NHP5G is an antagonist at the NR1/NR2A subtype but an agonist at the NR1/NR2D subtype. Molecular docking studies indicate that the substituent protrudes into a region that may be further exploited to improve subtype selectivity, thereby opening up a design strategy for ligands which can differentiate individual NMDA receptor subtypes.
|
Inhibition of [3H]D-Asp uptake at human EAAT3 in HEK293 cells
|
Homo sapiens
|
51.0
nM
|
|
Journal : J. Med. Chem.
Title : Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid: a novel selective inhibitor of human excitatory amino acid transporter subtype 2.
Year : 2008
Volume : 51
Issue : 14
First Page : 4085
Last Page : 4092
Authors : Sagot E, Jensen AA, Pickering DS, Pu X, Umberti M, Stensbøl TB, Nielsen B, Assaf Z, Aboab B, Bolte J, Gefflaut T, Bunch L.
Abstract : In the mammalian central nervous system (CNS), the action of sodium dependent excitatory amino acid transporters (EAATs) is responsible for termination of glutamatergic neurotransmission by reuptake of ( S) -glutamate (Glu) from the synaptic cleft. Five EAAT subtypes have been identified, of which EAAT1-4 are present in the CNS, while EAAT5 is localized exclusively in the retina. In this study, we have used an enantioselective chemo-enzymatic strategy to synthesize 10 new Glu analogues 2a- k ( 2d is exempt) with different functionalities in the 4 R-position and characterized their pharmacological properties at the human EAAT1-3. In particular, one compound, 2k, displayed a significant preference as inhibitor of the EAAT2 subtype over EAAT1,3. The compound also displayed very low affinities toward ionotropic and metabotropic Glu receptors, making it the most selective EAAT2 inhibitor described so far.
|
Displacement of [3H]SYM2081 from rat recombinant iGluR5
|
Rattus norvegicus
|
140.0
nM
|
|
Displacement of [3H]SYM2081 from rat recombinant iGluR5
|
Rattus norvegicus
|
138.04
nM
|
|
Journal : J. Med. Chem.
Title : Chemo-enzymatic synthesis of a series of 2,4-syn-functionalized (S)-glutamate analogues: new insight into the structure-activity relation of ionotropic glutamate receptor subtypes 5, 6, and 7.
Year : 2008
Volume : 51
Issue : 14
First Page : 4093
Last Page : 4103
Authors : Sagot E, Pickering DS, Pu X, Umberti M, Stensbøl TB, Nielsen B, Chapelet M, Bolte J, Gefflaut T, Bunch L.
Abstract : ( S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the central nervous system (CNS) activating the plethora of ionotropic Glu receptors (iGluRs) and metabotropic Glu receptors (mGluRs). In this paper, we present a chemo-enzymatic strategy for the enantioselective synthesis of five new Glu analogues 2a- f ( 2d is exempt) holding a functionalized substituent in the 4-position. Nine Glu analogues 2a- j are characterized pharmacologically at native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), kainic acid (KA), and N-methyl- d-aspartic acid (NMDA) receptors in rat synaptosomes as well as in binding assays at cloned rat iGluR5-7 subtypes. A detailed in silico study address as to why 2h is a high-affinity ligand at iGluR5-7 ( K i = 3.81, 123, 57.3 nM, respectively), while 2e is only a high affinity ligand at iGluR5 ( K i = 42.8 nM). Furthermore, a small series of commercially available iGluR ligands are characterized in iGluR5-7 binding.
|
Displacement of [3H]SYM2081 from rat recombinant iGluR6
|
Rattus norvegicus
|
331.0
nM
|
|
Displacement of [3H]SYM2081 from rat recombinant iGluR6
|
Rattus norvegicus
|
331.13
nM
|
|
Journal : J. Med. Chem.
Title : Chemo-enzymatic synthesis of a series of 2,4-syn-functionalized (S)-glutamate analogues: new insight into the structure-activity relation of ionotropic glutamate receptor subtypes 5, 6, and 7.
Year : 2008
Volume : 51
Issue : 14
First Page : 4093
Last Page : 4103
Authors : Sagot E, Pickering DS, Pu X, Umberti M, Stensbøl TB, Nielsen B, Chapelet M, Bolte J, Gefflaut T, Bunch L.
Abstract : ( S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the central nervous system (CNS) activating the plethora of ionotropic Glu receptors (iGluRs) and metabotropic Glu receptors (mGluRs). In this paper, we present a chemo-enzymatic strategy for the enantioselective synthesis of five new Glu analogues 2a- f ( 2d is exempt) holding a functionalized substituent in the 4-position. Nine Glu analogues 2a- j are characterized pharmacologically at native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), kainic acid (KA), and N-methyl- d-aspartic acid (NMDA) receptors in rat synaptosomes as well as in binding assays at cloned rat iGluR5-7 subtypes. A detailed in silico study address as to why 2h is a high-affinity ligand at iGluR5-7 ( K i = 3.81, 123, 57.3 nM, respectively), while 2e is only a high affinity ligand at iGluR5 ( K i = 42.8 nM). Furthermore, a small series of commercially available iGluR ligands are characterized in iGluR5-7 binding.
|
Displacement of [3H]SYM2081 from rat recombinant iGluR7
|
Rattus norvegicus
|
494.0
nM
|
|
Displacement of [3H]SYM2081 from rat recombinant iGluR7
|
Rattus norvegicus
|
489.78
nM
|
|
Journal : J. Med. Chem.
Title : Chemo-enzymatic synthesis of a series of 2,4-syn-functionalized (S)-glutamate analogues: new insight into the structure-activity relation of ionotropic glutamate receptor subtypes 5, 6, and 7.
Year : 2008
Volume : 51
Issue : 14
First Page : 4093
Last Page : 4103
Authors : Sagot E, Pickering DS, Pu X, Umberti M, Stensbøl TB, Nielsen B, Chapelet M, Bolte J, Gefflaut T, Bunch L.
Abstract : ( S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the central nervous system (CNS) activating the plethora of ionotropic Glu receptors (iGluRs) and metabotropic Glu receptors (mGluRs). In this paper, we present a chemo-enzymatic strategy for the enantioselective synthesis of five new Glu analogues 2a- f ( 2d is exempt) holding a functionalized substituent in the 4-position. Nine Glu analogues 2a- j are characterized pharmacologically at native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), kainic acid (KA), and N-methyl- d-aspartic acid (NMDA) receptors in rat synaptosomes as well as in binding assays at cloned rat iGluR5-7 subtypes. A detailed in silico study address as to why 2h is a high-affinity ligand at iGluR5-7 ( K i = 3.81, 123, 57.3 nM, respectively), while 2e is only a high affinity ligand at iGluR5 ( K i = 42.8 nM). Furthermore, a small series of commercially available iGluR ligands are characterized in iGluR5-7 binding.
|
Displacement of [3H]CGP39653 from NMDA receptor in Sprague-Dawley rat brain membrane
|
Rattus norvegicus
|
69.0
nM
|
|
Journal : J. Nat. Prod.
Title : Isolations of N-methyl-D-aspartic acid-type glutamate receptor ligands from Micronesian sponges.
Year : 2003
Volume : 66
Issue : 6
First Page : 784
Last Page : 787
Authors : Sakai R, Matsubara H, Shimamoto K, Jimbo M, Kamiya H, Namikoshi M.
Abstract : The bioassay-guided fractionation of the water-soluble extract of the marine sponge Cribrochalina olemda collected in Palau resulted in the isolation of a new amino acid cribronic acid (1): (2S,4R,5R)-5-hydroxy-4-sulfooxypiperidine-2-carboxylic acid. However, aqueous extracts of Stylotella aurantium and Axinella carteri collected in Yap State, Micronesia, afforded a known N-methyl-d-aspartic acid (NMDA)-type glutamate receptor agonist, (2S,4S)-4-sulfooxypiperidine-2-carboxylic acid (2), as a common active principle. Both 1 and 2 induced convulsive behaviors in mice upon intracerebroventricular (icv) injection with ED(50) values of 29 +/- 3.0 and 20 +/- 2.8 pmol/mouse, respectively. Radioligand binding assay using rat cerebrocortical membrane demonstrated that 1 and 2 inhibit the binding of the labeled NMDA receptor ligand [(3)H]CGP39653 at IC(50) values of 83 +/- 15 and 214 +/- 20 nM, respectively. However, 1 and 2 did not displace [(3)H]kainic acid or [(3)H]AMPA. These data indicated that 1 is a selective NMDA-type glutamate receptor ligand with potent convulsant activity in mice.
|
Displacement of (R,S)-[5-methyl-3H]AMPA from rat recombinant flop iGluR1 expressed in Sf9 cells
|
Rattus norvegicus
|
169.0
nM
|
|
Journal : J. Med. Chem.
Title : 1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. structure-activity relationships and identification of potent and Selective iGluR5 modulators.
Year : 2008
Volume : 51
Issue : 20
First Page : 6614
Last Page : 6618
Authors : Butini S, Pickering DS, Morelli E, Coccone SS, Trotta F, De Angelis M, Guarino E, Fiorini I, Campiani G, Novellino E, Schousboe A, Christensen JK, Gemma S.
Abstract : (S)-CPW399 ((S)-1) is a potent and excitotoxic AMPA receptor partial agonist. Modifying the cyclopentane ring of (S)-1, we developed two of the most potent and selective functional antagonists (5 and 7) for kainate receptor (KA-R) subunit iGluR5. Derivatives 5 and 7, with their unique pharmacological profile, may lead to a better understanding of the different roles and modes of action of iGluR1-5 subunits, paving the way for the synthesis of new potent, subunit selective iGluR5 modulators.
|
Displacement of (R,S)-[5-methyl-3H]AMPA from rat recombinant flop iGluR2(R) expressed in Sf9 cells
|
Rattus norvegicus
|
282.0
nM
|
|
Journal : J. Med. Chem.
Title : 1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. structure-activity relationships and identification of potent and Selective iGluR5 modulators.
Year : 2008
Volume : 51
Issue : 20
First Page : 6614
Last Page : 6618
Authors : Butini S, Pickering DS, Morelli E, Coccone SS, Trotta F, De Angelis M, Guarino E, Fiorini I, Campiani G, Novellino E, Schousboe A, Christensen JK, Gemma S.
Abstract : (S)-CPW399 ((S)-1) is a potent and excitotoxic AMPA receptor partial agonist. Modifying the cyclopentane ring of (S)-1, we developed two of the most potent and selective functional antagonists (5 and 7) for kainate receptor (KA-R) subunit iGluR5. Derivatives 5 and 7, with their unique pharmacological profile, may lead to a better understanding of the different roles and modes of action of iGluR1-5 subunits, paving the way for the synthesis of new potent, subunit selective iGluR5 modulators.
|
Displacement of (R,S)-[5-methyl-3H]AMPA from rat recombinant flop iGluR3 expressed in Sf9 cells
|
Rattus norvegicus
|
249.0
nM
|
|
Journal : J. Med. Chem.
Title : 1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. structure-activity relationships and identification of potent and Selective iGluR5 modulators.
Year : 2008
Volume : 51
Issue : 20
First Page : 6614
Last Page : 6618
Authors : Butini S, Pickering DS, Morelli E, Coccone SS, Trotta F, De Angelis M, Guarino E, Fiorini I, Campiani G, Novellino E, Schousboe A, Christensen JK, Gemma S.
Abstract : (S)-CPW399 ((S)-1) is a potent and excitotoxic AMPA receptor partial agonist. Modifying the cyclopentane ring of (S)-1, we developed two of the most potent and selective functional antagonists (5 and 7) for kainate receptor (KA-R) subunit iGluR5. Derivatives 5 and 7, with their unique pharmacological profile, may lead to a better understanding of the different roles and modes of action of iGluR1-5 subunits, paving the way for the synthesis of new potent, subunit selective iGluR5 modulators.
|
Displacement of (R,S)-[5-methyl-3H]AMPA from rat recombinant flop iGluR4 expressed in Sf9 cells
|
Rattus norvegicus
|
354.0
nM
|
|
Journal : J. Med. Chem.
Title : 1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. structure-activity relationships and identification of potent and Selective iGluR5 modulators.
Year : 2008
Volume : 51
Issue : 20
First Page : 6614
Last Page : 6618
Authors : Butini S, Pickering DS, Morelli E, Coccone SS, Trotta F, De Angelis M, Guarino E, Fiorini I, Campiani G, Novellino E, Schousboe A, Christensen JK, Gemma S.
Abstract : (S)-CPW399 ((S)-1) is a potent and excitotoxic AMPA receptor partial agonist. Modifying the cyclopentane ring of (S)-1, we developed two of the most potent and selective functional antagonists (5 and 7) for kainate receptor (KA-R) subunit iGluR5. Derivatives 5 and 7, with their unique pharmacological profile, may lead to a better understanding of the different roles and modes of action of iGluR1-5 subunits, paving the way for the synthesis of new potent, subunit selective iGluR5 modulators.
|
Displacement of [3H]SYM2081 from rat recombinant iGluR5(Q)1b expressed in Sf9 cells
|
Rattus norvegicus
|
140.0
nM
|
|
Journal : J. Med. Chem.
Title : 1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. structure-activity relationships and identification of potent and Selective iGluR5 modulators.
Year : 2008
Volume : 51
Issue : 20
First Page : 6614
Last Page : 6618
Authors : Butini S, Pickering DS, Morelli E, Coccone SS, Trotta F, De Angelis M, Guarino E, Fiorini I, Campiani G, Novellino E, Schousboe A, Christensen JK, Gemma S.
Abstract : (S)-CPW399 ((S)-1) is a potent and excitotoxic AMPA receptor partial agonist. Modifying the cyclopentane ring of (S)-1, we developed two of the most potent and selective functional antagonists (5 and 7) for kainate receptor (KA-R) subunit iGluR5. Derivatives 5 and 7, with their unique pharmacological profile, may lead to a better understanding of the different roles and modes of action of iGluR1-5 subunits, paving the way for the synthesis of new potent, subunit selective iGluR5 modulators.
|
Displacement of [3H]kainic acid from rat recombinant iGluR6(V,C,R) receptor expressed in Sf9 cells
|
Rattus norvegicus
|
332.0
nM
|
|
Journal : J. Med. Chem.
Title : 1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. structure-activity relationships and identification of potent and Selective iGluR5 modulators.
Year : 2008
Volume : 51
Issue : 20
First Page : 6614
Last Page : 6618
Authors : Butini S, Pickering DS, Morelli E, Coccone SS, Trotta F, De Angelis M, Guarino E, Fiorini I, Campiani G, Novellino E, Schousboe A, Christensen JK, Gemma S.
Abstract : (S)-CPW399 ((S)-1) is a potent and excitotoxic AMPA receptor partial agonist. Modifying the cyclopentane ring of (S)-1, we developed two of the most potent and selective functional antagonists (5 and 7) for kainate receptor (KA-R) subunit iGluR5. Derivatives 5 and 7, with their unique pharmacological profile, may lead to a better understanding of the different roles and modes of action of iGluR1-5 subunits, paving the way for the synthesis of new potent, subunit selective iGluR5 modulators.
|
Displacement of [3H]CGP39653 from NMDA receptor in rat brain membranes
|
Rattus norvegicus
|
290.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of novel bicyclo[1.1.1]pentane-based omega-acidic amino acids as glutamate receptors ligands.
Year : 2009
Volume : 17
Issue : 1
First Page : 242
Last Page : 250
Authors : Filosa R, Carmela Fulco M, Marinozzi M, Giacchè N, Macchiarulo A, Peduto A, Massa A, de Caprariis P, Thomsen C, Christoffersen CT, Pellicciari R.
Abstract : A novel series of bicyclo[1.1.1]pentane-based omega-acidic amino acids, including (2S)- and (2R)-3-(3'-carboxybicyclo[1.1.1]pentyl)alanines (8 and 9), (2S)- and (2R)-2-(3'-carboxymethylbicyclo[1.1.1]pentyl)glycines (10 and 11), and (2S)- and (2R)-3-(3'-phosphonomethylbicyclo[1.1.1]pentyl)glycines (12 and 13), were synthesized and evaluated as glutamate receptor ligands. Among them, (2R)-3-(3'-phosphonomethylbicyclo[1.1.1]pentyl)glycine (13) showed relatively high affinity and selectivity at the NMDA receptor. The results are also discussed in light of pharmacophoric modelling studies of NMDA agonists and antagonists.
|
Displacement of [3H]AMPA from AMPA receptor in rat brain membranes
|
Rattus norvegicus
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of novel bicyclo[1.1.1]pentane-based omega-acidic amino acids as glutamate receptors ligands.
Year : 2009
Volume : 17
Issue : 1
First Page : 242
Last Page : 250
Authors : Filosa R, Carmela Fulco M, Marinozzi M, Giacchè N, Macchiarulo A, Peduto A, Massa A, de Caprariis P, Thomsen C, Christoffersen CT, Pellicciari R.
Abstract : A novel series of bicyclo[1.1.1]pentane-based omega-acidic amino acids, including (2S)- and (2R)-3-(3'-carboxybicyclo[1.1.1]pentyl)alanines (8 and 9), (2S)- and (2R)-2-(3'-carboxymethylbicyclo[1.1.1]pentyl)glycines (10 and 11), and (2S)- and (2R)-3-(3'-phosphonomethylbicyclo[1.1.1]pentyl)glycines (12 and 13), were synthesized and evaluated as glutamate receptor ligands. Among them, (2R)-3-(3'-phosphonomethylbicyclo[1.1.1]pentyl)glycine (13) showed relatively high affinity and selectivity at the NMDA receptor. The results are also discussed in light of pharmacophoric modelling studies of NMDA agonists and antagonists.
|
Displacement of [3H]kainic acid from kainate receptor in rat brain membranes
|
Rattus norvegicus
|
92.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of novel bicyclo[1.1.1]pentane-based omega-acidic amino acids as glutamate receptors ligands.
Year : 2009
Volume : 17
Issue : 1
First Page : 242
Last Page : 250
Authors : Filosa R, Carmela Fulco M, Marinozzi M, Giacchè N, Macchiarulo A, Peduto A, Massa A, de Caprariis P, Thomsen C, Christoffersen CT, Pellicciari R.
Abstract : A novel series of bicyclo[1.1.1]pentane-based omega-acidic amino acids, including (2S)- and (2R)-3-(3'-carboxybicyclo[1.1.1]pentyl)alanines (8 and 9), (2S)- and (2R)-2-(3'-carboxymethylbicyclo[1.1.1]pentyl)glycines (10 and 11), and (2S)- and (2R)-3-(3'-phosphonomethylbicyclo[1.1.1]pentyl)glycines (12 and 13), were synthesized and evaluated as glutamate receptor ligands. Among them, (2R)-3-(3'-phosphonomethylbicyclo[1.1.1]pentyl)glycine (13) showed relatively high affinity and selectivity at the NMDA receptor. The results are also discussed in light of pharmacophoric modelling studies of NMDA agonists and antagonists.
|
Displacement of [3H]Quisqualate from human mGluR1A receptor expressed in BHK cells
|
Homo sapiens
|
570.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of novel bicyclo[1.1.1]pentane-based omega-acidic amino acids as glutamate receptors ligands.
Year : 2009
Volume : 17
Issue : 1
First Page : 242
Last Page : 250
Authors : Filosa R, Carmela Fulco M, Marinozzi M, Giacchè N, Macchiarulo A, Peduto A, Massa A, de Caprariis P, Thomsen C, Christoffersen CT, Pellicciari R.
Abstract : A novel series of bicyclo[1.1.1]pentane-based omega-acidic amino acids, including (2S)- and (2R)-3-(3'-carboxybicyclo[1.1.1]pentyl)alanines (8 and 9), (2S)- and (2R)-2-(3'-carboxymethylbicyclo[1.1.1]pentyl)glycines (10 and 11), and (2S)- and (2R)-3-(3'-phosphonomethylbicyclo[1.1.1]pentyl)glycines (12 and 13), were synthesized and evaluated as glutamate receptor ligands. Among them, (2R)-3-(3'-phosphonomethylbicyclo[1.1.1]pentyl)glycine (13) showed relatively high affinity and selectivity at the NMDA receptor. The results are also discussed in light of pharmacophoric modelling studies of NMDA agonists and antagonists.
|
Displacement of [3H]AMPA from AMPA receptor in Sprague-Dawley rat brain membranes
|
Rattus norvegicus
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues.
Year : 2010
Volume : 53
Issue : 10
First Page : 4110
Last Page : 4118
Authors : Lolli ML, Giordano C, Pickering DS, Rolando B, Hansen KB, Foti A, Contreras-Sanz A, Amir A, Fruttero R, Gasco A, Nielsen B, Johansen TN.
Abstract : In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic alpha-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC(50) = 10 microM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.
|
Displacement of [3H]KA from KA receptor in Sprague-Dawley rat brain membranes
|
Rattus norvegicus
|
380.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues.
Year : 2010
Volume : 53
Issue : 10
First Page : 4110
Last Page : 4118
Authors : Lolli ML, Giordano C, Pickering DS, Rolando B, Hansen KB, Foti A, Contreras-Sanz A, Amir A, Fruttero R, Gasco A, Nielsen B, Johansen TN.
Abstract : In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic alpha-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC(50) = 10 microM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.
|
Displacement of [3H]CGP39653 from NMDA receptor in Sprague-Dawley rat brain membranes
|
Rattus norvegicus
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues.
Year : 2010
Volume : 53
Issue : 10
First Page : 4110
Last Page : 4118
Authors : Lolli ML, Giordano C, Pickering DS, Rolando B, Hansen KB, Foti A, Contreras-Sanz A, Amir A, Fruttero R, Gasco A, Nielsen B, Johansen TN.
Abstract : In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic alpha-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC(50) = 10 microM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.
|
Displacement of [3H]AMPA from rat iGluR2 receptor expressed in Sf9 cells baculovirus system after 1 to 2 hrs by liquid scintillation counting
|
Rattus norvegicus
|
280.0
nM
|
|
Displacement of [3H]AMPA from rat iGluR2 receptor expressed in Sf9 cells baculovirus system after 1 to 2 hrs by liquid scintillation counting
|
Rattus norvegicus
|
281.84
nM
|
|
Journal : J. Med. Chem.
Title : 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues.
Year : 2010
Volume : 53
Issue : 10
First Page : 4110
Last Page : 4118
Authors : Lolli ML, Giordano C, Pickering DS, Rolando B, Hansen KB, Foti A, Contreras-Sanz A, Amir A, Fruttero R, Gasco A, Nielsen B, Johansen TN.
Abstract : In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic alpha-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC(50) = 10 microM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.
|
Displacement of [3H]SYM2081 from rat iGluR5 receptor expressed in Sf9 cells baculovirus system after 1 to 2 hrs by liquid scintillation counting
|
Rattus norvegicus
|
140.0
nM
|
|
Displacement of [3H]SYM2081 from rat iGluR5 receptor expressed in Sf9 cells baculovirus system after 1 to 2 hrs by liquid scintillation counting
|
Rattus norvegicus
|
138.04
nM
|
|
Journal : J. Med. Chem.
Title : 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues.
Year : 2010
Volume : 53
Issue : 10
First Page : 4110
Last Page : 4118
Authors : Lolli ML, Giordano C, Pickering DS, Rolando B, Hansen KB, Foti A, Contreras-Sanz A, Amir A, Fruttero R, Gasco A, Nielsen B, Johansen TN.
Abstract : In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic alpha-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC(50) = 10 microM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.
|
Displacement of [3H]SYM2081 from rat iGluR6 receptor expressed in Sf9 cells baculovirus system after 1 to 2 hrs by liquid scintillation counting
|
Rattus norvegicus
|
330.0
nM
|
|
Displacement of [3H]SYM2081 from rat iGluR6 receptor expressed in Sf9 cells baculovirus system after 1 to 2 hrs by liquid scintillation counting
|
Rattus norvegicus
|
331.13
nM
|
|
Journal : J. Med. Chem.
Title : 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues.
Year : 2010
Volume : 53
Issue : 10
First Page : 4110
Last Page : 4118
Authors : Lolli ML, Giordano C, Pickering DS, Rolando B, Hansen KB, Foti A, Contreras-Sanz A, Amir A, Fruttero R, Gasco A, Nielsen B, Johansen TN.
Abstract : In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic alpha-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC(50) = 10 microM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.
|
Displacement of [3H]SYM2081 from rat iGluR7 receptor expressed in Sf9 cells baculovirus system after 1 to 2 hrs by liquid scintillation counting
|
Rattus norvegicus
|
490.0
nM
|
|
Displacement of [3H]SYM2081 from rat iGluR7 receptor expressed in Sf9 cells baculovirus system after 1 to 2 hrs by liquid scintillation counting
|
Rattus norvegicus
|
489.78
nM
|
|
Journal : J. Med. Chem.
Title : 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues.
Year : 2010
Volume : 53
Issue : 10
First Page : 4110
Last Page : 4118
Authors : Lolli ML, Giordano C, Pickering DS, Rolando B, Hansen KB, Foti A, Contreras-Sanz A, Amir A, Fruttero R, Gasco A, Nielsen B, Johansen TN.
Abstract : In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic alpha-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC(50) = 10 microM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.
|
Antagonist activity at NMDA receptor (unknwon origin)
|
Homo sapiens
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : Synopsis of some recent tactical application of bioisosteres in drug design.
Year : 2011
Volume : 54
Issue : 8
First Page : 2529
Last Page : 2591
Authors : Meanwell NA.
|
Binding affinity to full length rat GluA3
|
Rattus norvegicus
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Chemoenzymatic synthesis of new 2,4-syn-functionalized (S)-glutamate analogues and structure-activity relationship studies at ionotropic glutamate receptors and excitatory amino acid transporters.
Year : 2013
Volume : 56
Issue : 4
First Page : 1614
Last Page : 1628
Authors : Assaf Z, Larsen AP, Venskutonytė R, Han L, Abrahamsen B, Nielsen B, Gajhede M, Kastrup JS, Jensen AA, Pickering DS, Frydenvang K, Gefflaut T, Bunch L.
Abstract : In the mammalian central nervous system, (S)-glutamate (Glu) is released from the presynaptic neuron where it activates a plethora of pre- and postsynaptic Glu receptors. The fast acting ionotropic Glu receptors (iGluRs) are ligand gated ion channels and are believed to be involved in a vast number of neurological functions such as memory and learning, synaptic plasticity, and motor function. The synthesis of 14 enantiopure 2,4-syn-Glu analogues 2b-p is accessed by a short and efficient chemoenzymatic approach starting from readily available cyclohexanone 3. Pharmacological characterization at the iGluRs and EAAT1-3 subtypes revealed analogue 2i as a selective GluK1 ligand with low nanomolar affinity. Two X-ray crystal structures of the key analogue 2i in the ligand-binding domain (LBD) of GluA2 and GluK3 were determined. Partial domain closure was seen in the GluA2-LBD complex with 2i comparable to that induced by kainate. In contrast, full domain closure was observed in the GluK3-LBD complex with 2i, similar to that of GluK3-LBD with glutamate bound.
|
Displacement of [3H]-(2S,4R)-4-methylglutamic acid from full length recombinant rat GluK3 receptor expressed in sf9 cells by liquid scintillation counting
|
Rattus norvegicus
|
494.0
nM
|
|
Journal : J. Med. Chem.
Title : Chemoenzymatic synthesis of new 2,4-syn-functionalized (S)-glutamate analogues and structure-activity relationship studies at ionotropic glutamate receptors and excitatory amino acid transporters.
Year : 2013
Volume : 56
Issue : 4
First Page : 1614
Last Page : 1628
Authors : Assaf Z, Larsen AP, Venskutonytė R, Han L, Abrahamsen B, Nielsen B, Gajhede M, Kastrup JS, Jensen AA, Pickering DS, Frydenvang K, Gefflaut T, Bunch L.
Abstract : In the mammalian central nervous system, (S)-glutamate (Glu) is released from the presynaptic neuron where it activates a plethora of pre- and postsynaptic Glu receptors. The fast acting ionotropic Glu receptors (iGluRs) are ligand gated ion channels and are believed to be involved in a vast number of neurological functions such as memory and learning, synaptic plasticity, and motor function. The synthesis of 14 enantiopure 2,4-syn-Glu analogues 2b-p is accessed by a short and efficient chemoenzymatic approach starting from readily available cyclohexanone 3. Pharmacological characterization at the iGluRs and EAAT1-3 subtypes revealed analogue 2i as a selective GluK1 ligand with low nanomolar affinity. Two X-ray crystal structures of the key analogue 2i in the ligand-binding domain (LBD) of GluA2 and GluK3 were determined. Partial domain closure was seen in the GluA2-LBD complex with 2i comparable to that induced by kainate. In contrast, full domain closure was observed in the GluK3-LBD complex with 2i, similar to that of GluK3-LBD with glutamate bound.
|
Displacement of [3H]-(2S,4R)-4-methylglutamic acid from full length recombinant rat GluKK2(VCR) receptor expressed in sf9 cells by liquid scintillation counting
|
Rattus norvegicus
|
331.0
nM
|
|
Journal : J. Med. Chem.
Title : Chemoenzymatic synthesis of new 2,4-syn-functionalized (S)-glutamate analogues and structure-activity relationship studies at ionotropic glutamate receptors and excitatory amino acid transporters.
Year : 2013
Volume : 56
Issue : 4
First Page : 1614
Last Page : 1628
Authors : Assaf Z, Larsen AP, Venskutonytė R, Han L, Abrahamsen B, Nielsen B, Gajhede M, Kastrup JS, Jensen AA, Pickering DS, Frydenvang K, Gefflaut T, Bunch L.
Abstract : In the mammalian central nervous system, (S)-glutamate (Glu) is released from the presynaptic neuron where it activates a plethora of pre- and postsynaptic Glu receptors. The fast acting ionotropic Glu receptors (iGluRs) are ligand gated ion channels and are believed to be involved in a vast number of neurological functions such as memory and learning, synaptic plasticity, and motor function. The synthesis of 14 enantiopure 2,4-syn-Glu analogues 2b-p is accessed by a short and efficient chemoenzymatic approach starting from readily available cyclohexanone 3. Pharmacological characterization at the iGluRs and EAAT1-3 subtypes revealed analogue 2i as a selective GluK1 ligand with low nanomolar affinity. Two X-ray crystal structures of the key analogue 2i in the ligand-binding domain (LBD) of GluA2 and GluK3 were determined. Partial domain closure was seen in the GluA2-LBD complex with 2i comparable to that induced by kainate. In contrast, full domain closure was observed in the GluK3-LBD complex with 2i, similar to that of GluK3-LBD with glutamate bound.
|
Displacement of [3H]-(2S,4R)-4-methylglutamic acid from full length recombinant rat GluKK1(Q)1b receptor expressed in sf9 cells by liquid scintillation counting
|
Rattus norvegicus
|
140.0
nM
|
|
Journal : J. Med. Chem.
Title : Chemoenzymatic synthesis of new 2,4-syn-functionalized (S)-glutamate analogues and structure-activity relationship studies at ionotropic glutamate receptors and excitatory amino acid transporters.
Year : 2013
Volume : 56
Issue : 4
First Page : 1614
Last Page : 1628
Authors : Assaf Z, Larsen AP, Venskutonytė R, Han L, Abrahamsen B, Nielsen B, Gajhede M, Kastrup JS, Jensen AA, Pickering DS, Frydenvang K, Gefflaut T, Bunch L.
Abstract : In the mammalian central nervous system, (S)-glutamate (Glu) is released from the presynaptic neuron where it activates a plethora of pre- and postsynaptic Glu receptors. The fast acting ionotropic Glu receptors (iGluRs) are ligand gated ion channels and are believed to be involved in a vast number of neurological functions such as memory and learning, synaptic plasticity, and motor function. The synthesis of 14 enantiopure 2,4-syn-Glu analogues 2b-p is accessed by a short and efficient chemoenzymatic approach starting from readily available cyclohexanone 3. Pharmacological characterization at the iGluRs and EAAT1-3 subtypes revealed analogue 2i as a selective GluK1 ligand with low nanomolar affinity. Two X-ray crystal structures of the key analogue 2i in the ligand-binding domain (LBD) of GluA2 and GluK3 were determined. Partial domain closure was seen in the GluA2-LBD complex with 2i comparable to that induced by kainate. In contrast, full domain closure was observed in the GluK3-LBD complex with 2i, similar to that of GluK3-LBD with glutamate bound.
|
Displacement of [3H]AMPA from full length recombinant rat GluKA2(R) receptor expressed in sf9 cells by liquid scintillation counting
|
Rattus norvegicus
|
282.0
nM
|
|
Journal : J. Med. Chem.
Title : Chemoenzymatic synthesis of new 2,4-syn-functionalized (S)-glutamate analogues and structure-activity relationship studies at ionotropic glutamate receptors and excitatory amino acid transporters.
Year : 2013
Volume : 56
Issue : 4
First Page : 1614
Last Page : 1628
Authors : Assaf Z, Larsen AP, Venskutonytė R, Han L, Abrahamsen B, Nielsen B, Gajhede M, Kastrup JS, Jensen AA, Pickering DS, Frydenvang K, Gefflaut T, Bunch L.
Abstract : In the mammalian central nervous system, (S)-glutamate (Glu) is released from the presynaptic neuron where it activates a plethora of pre- and postsynaptic Glu receptors. The fast acting ionotropic Glu receptors (iGluRs) are ligand gated ion channels and are believed to be involved in a vast number of neurological functions such as memory and learning, synaptic plasticity, and motor function. The synthesis of 14 enantiopure 2,4-syn-Glu analogues 2b-p is accessed by a short and efficient chemoenzymatic approach starting from readily available cyclohexanone 3. Pharmacological characterization at the iGluRs and EAAT1-3 subtypes revealed analogue 2i as a selective GluK1 ligand with low nanomolar affinity. Two X-ray crystal structures of the key analogue 2i in the ligand-binding domain (LBD) of GluA2 and GluK3 were determined. Partial domain closure was seen in the GluA2-LBD complex with 2i comparable to that induced by kainate. In contrast, full domain closure was observed in the GluK3-LBD complex with 2i, similar to that of GluK3-LBD with glutamate bound.
|
Displacement of [3H]CGP39653 from NMDA receptor in rat brain cortex after 60 mins by Packard TopCount microplate scintillator counting
|
Rattus norvegicus
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Chemoenzymatic synthesis of new 2,4-syn-functionalized (S)-glutamate analogues and structure-activity relationship studies at ionotropic glutamate receptors and excitatory amino acid transporters.
Year : 2013
Volume : 56
Issue : 4
First Page : 1614
Last Page : 1628
Authors : Assaf Z, Larsen AP, Venskutonytė R, Han L, Abrahamsen B, Nielsen B, Gajhede M, Kastrup JS, Jensen AA, Pickering DS, Frydenvang K, Gefflaut T, Bunch L.
Abstract : In the mammalian central nervous system, (S)-glutamate (Glu) is released from the presynaptic neuron where it activates a plethora of pre- and postsynaptic Glu receptors. The fast acting ionotropic Glu receptors (iGluRs) are ligand gated ion channels and are believed to be involved in a vast number of neurological functions such as memory and learning, synaptic plasticity, and motor function. The synthesis of 14 enantiopure 2,4-syn-Glu analogues 2b-p is accessed by a short and efficient chemoenzymatic approach starting from readily available cyclohexanone 3. Pharmacological characterization at the iGluRs and EAAT1-3 subtypes revealed analogue 2i as a selective GluK1 ligand with low nanomolar affinity. Two X-ray crystal structures of the key analogue 2i in the ligand-binding domain (LBD) of GluA2 and GluK3 were determined. Partial domain closure was seen in the GluA2-LBD complex with 2i comparable to that induced by kainate. In contrast, full domain closure was observed in the GluK3-LBD complex with 2i, similar to that of GluK3-LBD with glutamate bound.
|
Displacement of [3H]KA from kainate receptor in rat brain cortex after 60 mins by Packard TopCount microplate scintillator counting
|
Rattus norvegicus
|
380.0
nM
|
|
Journal : J. Med. Chem.
Title : Chemoenzymatic synthesis of new 2,4-syn-functionalized (S)-glutamate analogues and structure-activity relationship studies at ionotropic glutamate receptors and excitatory amino acid transporters.
Year : 2013
Volume : 56
Issue : 4
First Page : 1614
Last Page : 1628
Authors : Assaf Z, Larsen AP, Venskutonytė R, Han L, Abrahamsen B, Nielsen B, Gajhede M, Kastrup JS, Jensen AA, Pickering DS, Frydenvang K, Gefflaut T, Bunch L.
Abstract : In the mammalian central nervous system, (S)-glutamate (Glu) is released from the presynaptic neuron where it activates a plethora of pre- and postsynaptic Glu receptors. The fast acting ionotropic Glu receptors (iGluRs) are ligand gated ion channels and are believed to be involved in a vast number of neurological functions such as memory and learning, synaptic plasticity, and motor function. The synthesis of 14 enantiopure 2,4-syn-Glu analogues 2b-p is accessed by a short and efficient chemoenzymatic approach starting from readily available cyclohexanone 3. Pharmacological characterization at the iGluRs and EAAT1-3 subtypes revealed analogue 2i as a selective GluK1 ligand with low nanomolar affinity. Two X-ray crystal structures of the key analogue 2i in the ligand-binding domain (LBD) of GluA2 and GluK3 were determined. Partial domain closure was seen in the GluA2-LBD complex with 2i comparable to that induced by kainate. In contrast, full domain closure was observed in the GluK3-LBD complex with 2i, similar to that of GluK3-LBD with glutamate bound.
|
Displacement of [3H]AMPA from AMPA receptor in rat brain cortex after 30 mins by Packard TopCount microplate scintillator counting
|
Rattus norvegicus
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : Chemoenzymatic synthesis of new 2,4-syn-functionalized (S)-glutamate analogues and structure-activity relationship studies at ionotropic glutamate receptors and excitatory amino acid transporters.
Year : 2013
Volume : 56
Issue : 4
First Page : 1614
Last Page : 1628
Authors : Assaf Z, Larsen AP, Venskutonytė R, Han L, Abrahamsen B, Nielsen B, Gajhede M, Kastrup JS, Jensen AA, Pickering DS, Frydenvang K, Gefflaut T, Bunch L.
Abstract : In the mammalian central nervous system, (S)-glutamate (Glu) is released from the presynaptic neuron where it activates a plethora of pre- and postsynaptic Glu receptors. The fast acting ionotropic Glu receptors (iGluRs) are ligand gated ion channels and are believed to be involved in a vast number of neurological functions such as memory and learning, synaptic plasticity, and motor function. The synthesis of 14 enantiopure 2,4-syn-Glu analogues 2b-p is accessed by a short and efficient chemoenzymatic approach starting from readily available cyclohexanone 3. Pharmacological characterization at the iGluRs and EAAT1-3 subtypes revealed analogue 2i as a selective GluK1 ligand with low nanomolar affinity. Two X-ray crystal structures of the key analogue 2i in the ligand-binding domain (LBD) of GluA2 and GluK3 were determined. Partial domain closure was seen in the GluA2-LBD complex with 2i comparable to that induced by kainate. In contrast, full domain closure was observed in the GluK3-LBD complex with 2i, similar to that of GluK3-LBD with glutamate bound.
|
Displacement of [3H]Kainic acid from kainate receptor in Wistar rat brain after 60 mins
|
Rattus norvegicus
|
170.0
nM
|
|
Displacement of [3H]Kainic acid from kainate receptor in Wistar rat brain after 60 mins
|
Rattus norvegicus
|
240.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
|
Displacement of [3H]CGP 39653 from NMDA receptor agonist binding site in Wistar rat cerebral cortex after 20 mins
|
Rattus norvegicus
|
370.0
nM
|
|
Displacement of [3H]CGP 39653 from NMDA receptor agonist binding site in Wistar rat cerebral cortex after 20 mins
|
Rattus norvegicus
|
410.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
|
Displacement of [3H]CGP39653 from NMDA receptor agonist binding site in Wistar rat cerebral cortex at 10 uM after 20 mins relative to control
|
Rattus norvegicus
|
10.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
|
Displacement of [3H]Kainic acid from kainate receptor in Wistar rat brain at 10 uM after 60 mins relative to control
|
Rattus norvegicus
|
0.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
|
Displacement of [3H]-AMPA from AMPA receptor in rat brain cortical membranes
|
Rattus norvegicus
|
340.0
nM
|
|
Journal : MedChemComm
Title : A highly selective agonist for the metabotropic glutamate receptor mGluR2
Year : 2011
Volume : 2
Issue : 11
First Page : 1120
Last Page : 1124
Authors : Nielsen SD, Fulco M, Serpi M, Nielsen B, Hansen MB, Hansen KL, Thomsen C, Brodbeck R, Brauner-Osborne H, Pellicciari R, Norrby P, Greenwood JR, Clausen RP
|
Displacement of [3H]-KA from kainate receptor in rat brain cortical membranes
|
Rattus norvegicus
|
380.0
nM
|
|
Journal : MedChemComm
Title : A highly selective agonist for the metabotropic glutamate receptor mGluR2
Year : 2011
Volume : 2
Issue : 11
First Page : 1120
Last Page : 1124
Authors : Nielsen SD, Fulco M, Serpi M, Nielsen B, Hansen MB, Hansen KL, Thomsen C, Brodbeck R, Brauner-Osborne H, Pellicciari R, Norrby P, Greenwood JR, Clausen RP
|
Displacement of [3H]CGP-39653 from NMDA receptor in rat brain cortical membranes
|
Rattus norvegicus
|
200.0
nM
|
|
Journal : MedChemComm
Title : A highly selective agonist for the metabotropic glutamate receptor mGluR2
Year : 2011
Volume : 2
Issue : 11
First Page : 1120
Last Page : 1124
Authors : Nielsen SD, Fulco M, Serpi M, Nielsen B, Hansen MB, Hansen KL, Thomsen C, Brodbeck R, Brauner-Osborne H, Pellicciari R, Norrby P, Greenwood JR, Clausen RP
|
Agonist activity at human mGluR3 receptor expressed in HEK cells
|
Homo sapiens
|
60.0
nM
|
|
Journal : MedChemComm
Title : A highly selective agonist for the metabotropic glutamate receptor mGluR2
Year : 2011
Volume : 2
Issue : 11
First Page : 1120
Last Page : 1124
Authors : Nielsen SD, Fulco M, Serpi M, Nielsen B, Hansen MB, Hansen KL, Thomsen C, Brodbeck R, Brauner-Osborne H, Pellicciari R, Norrby P, Greenwood JR, Clausen RP
|
Binding affinity to human mGluR3 receptor expressed in HEK cells
|
Homo sapiens
|
57.54
nM
|
|
Journal : MedChemComm
Title : A highly selective agonist for the metabotropic glutamate receptor mGluR2
Year : 2011
Volume : 2
Issue : 11
First Page : 1120
Last Page : 1124
Authors : Nielsen SD, Fulco M, Serpi M, Nielsen B, Hansen MB, Hansen KL, Thomsen C, Brodbeck R, Brauner-Osborne H, Pellicciari R, Norrby P, Greenwood JR, Clausen RP
|
Displacement of [3H]AMPA from AMPA receptor in rat cortical synaptosomes
|
Rattus norvegicus
|
340.0
nM
|
|
Journal : MedChemComm
Title : Substituted 4-hydroxy-1,2,3-triazoles: synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches
Year : 2015
Volume : 6
Issue : 7
First Page : 1285
Last Page : 1292
Authors : Pippione AC, Dosio F, Ducime A, Federico A, Martina K, Sainas S, Frlund B, Gooyit M, Janda KD, Boschi D, Lolli ML
|
Displacement of [3H]KA from Kainate receptor in rat cortical synaptosomes
|
Rattus norvegicus
|
380.0
nM
|
|
Journal : MedChemComm
Title : Substituted 4-hydroxy-1,2,3-triazoles: synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches
Year : 2015
Volume : 6
Issue : 7
First Page : 1285
Last Page : 1292
Authors : Pippione AC, Dosio F, Ducime A, Federico A, Martina K, Sainas S, Frlund B, Gooyit M, Janda KD, Boschi D, Lolli ML
|
Displacement of [3H]CGP39653 from NMDA receptor in rat cortical synaptosomes
|
Rattus norvegicus
|
200.0
nM
|
|
Journal : MedChemComm
Title : Substituted 4-hydroxy-1,2,3-triazoles: synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches
Year : 2015
Volume : 6
Issue : 7
First Page : 1285
Last Page : 1292
Authors : Pippione AC, Dosio F, Ducime A, Federico A, Martina K, Sainas S, Frlund B, Gooyit M, Janda KD, Boschi D, Lolli ML
|
Agonist activity at rat mGlu3 receptor expressed in HEK293 cells by [35S]GTP-gamma binding assay
|
Rattus norvegicus
|
57.54
nM
|
|
Agonist activity at rat mGlu3 receptor expressed in HEK293 cells by [35S]GTP-gamma binding assay
|
Rattus norvegicus
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : New 4-Functionalized Glutamate Analogues Are Selective Agonists at Metabotropic Glutamate Receptor Subtype 2 or Selective Agonists at Metabotropic Glutamate Receptor Group III.
Year : 2016
Volume : 59
Issue : 3
First Page : 914
Last Page : 924
Authors : Huynh TH, Erichsen MN, Tora AS, Goudet C, Sagot E, Assaf Z, Thomsen C, Brodbeck R, Stensbøl TB, Bjørn-Yoshimoto WE, Nielsen B, Pin JP, Gefflaut T, Bunch L.
Abstract : The metabotropic glutamate (Glu) receptors (mGluRs) play key roles in modulating excitatory neurotransmission in the brain. In all, eight subtypes have been identified and divided into three groups, group I (mGlu1,5), group II (mGlu2,3), and group III (mGlu4,6-8). In this article, we present a L-2,4-syn-substituted Glu analogue, 1d, which displays selective agonist activity at mGlu2 over the remaining mGluR subtypes. A modeling study and redesign of the core scaffold led to the stereoselective synthesis of four new conformationally restricted Glu analogues, 2a-d. Most interestingly, 2a retained a selective agonist activity profile at mGlu2 (EC50 in the micromolar range), whereas 2c/2d were both selective agonists at group III, subtypes mGlu4,6,8. In general, 2d was 20-fold more potent than 2c and potently activated mGlu4,6,8 in the low-mid nanomolar range.
|
Cis-inhibition of human LAT1 expressed in TREx HEK293 cells at 200 uM assessed as inhibition of [3H]-gabapentin uptake at 200 uM preincubated for 3 mins at 37 degC followed by washing with choline buffer and measured after 3 hrs by scintillation counting analysis relative to BCH
|
Homo sapiens
|
-2.4
%
|
|
Journal : J Med Chem
Title : Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1).
Year : 2018
Volume : 61
Issue : 16
First Page : 7358
Last Page : 7373
Authors : Chien HC, Colas C, Finke K, Springer S, Stoner L, Zur AA, Venteicher B, Campbell J, Hall C, Flint A, Augustyn E, Hernandez C, Heeren N, Hansen L, Anthony A, Bauer J, Fotiadis D, Schlessinger A, Giacomini KM, Thomas AA.
Abstract : The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.
|
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
|
4.15
%
|
|
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.
|
Displacement of [3H]AMPA from AMPA receptor in rat brain synaptic cortical membranes after 30 mins by scintillation counting method
|
Rattus norvegicus
|
340.0
nM
|
|
Journal : J Med Chem
Title : Use of the 4-Hydroxytriazole Moiety as a Bioisosteric Tool in the Development of Ionotropic Glutamate Receptor Ligands.
Year : 2019
Volume : 62
Issue : 9
First Page : 4467
Last Page : 4482
Authors : Sainas S, Temperini P, Farnsworth JC, Yi F, Møllerud S, Jensen AA, Nielsen B, Passoni A, Kastrup JS, Hansen KB, Boschi D, Pickering DS, Clausen RP, Lolli ML.
Abstract : We report a series of glutamate and aspartate analogues designed using the hydroxy-1,2,3-triazole moiety as a bioisostere for the distal carboxylic acid. Compound 6b showed unprecedented selectivity among ( S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtypes, confirmed also by an unusual binding mode observed for the crystal structures in complex with the AMPA receptor GluA2 agonist-binding domain. Here, a methionine (Met729) was highly disordered compared to previous agonist-bound structures. This observation provides a possible explanation for the pharmacological profile. In the structure with 7a, an unusual organization of water molecules around the bioisostere arises compared to previous structures of ligands with other bioisosteres. Aspartate analogue 8 with the hydroxy-1,2,3-triazole moiety directly attached to glycine was unexpectedly able to activate both the glutamate and glycine agonist-binding sites of the N-methyl-d-aspartic acid receptor. These observations demonstrate novel features that arise when employing a hydroxytriazole moiety as a bioisostere for the distal carboxylic acid in glutamate receptor agonists.
|
Displacement of [3H]KA from KA receptor in rat brain synaptic cortical membranes after 60 mins by scintillation counting method
|
Rattus norvegicus
|
380.0
nM
|
|
Journal : J Med Chem
Title : Use of the 4-Hydroxytriazole Moiety as a Bioisosteric Tool in the Development of Ionotropic Glutamate Receptor Ligands.
Year : 2019
Volume : 62
Issue : 9
First Page : 4467
Last Page : 4482
Authors : Sainas S, Temperini P, Farnsworth JC, Yi F, Møllerud S, Jensen AA, Nielsen B, Passoni A, Kastrup JS, Hansen KB, Boschi D, Pickering DS, Clausen RP, Lolli ML.
Abstract : We report a series of glutamate and aspartate analogues designed using the hydroxy-1,2,3-triazole moiety as a bioisostere for the distal carboxylic acid. Compound 6b showed unprecedented selectivity among ( S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtypes, confirmed also by an unusual binding mode observed for the crystal structures in complex with the AMPA receptor GluA2 agonist-binding domain. Here, a methionine (Met729) was highly disordered compared to previous agonist-bound structures. This observation provides a possible explanation for the pharmacological profile. In the structure with 7a, an unusual organization of water molecules around the bioisostere arises compared to previous structures of ligands with other bioisosteres. Aspartate analogue 8 with the hydroxy-1,2,3-triazole moiety directly attached to glycine was unexpectedly able to activate both the glutamate and glycine agonist-binding sites of the N-methyl-d-aspartic acid receptor. These observations demonstrate novel features that arise when employing a hydroxytriazole moiety as a bioisostere for the distal carboxylic acid in glutamate receptor agonists.
|
Displacement of [3H]CGP39653 from NMDA receptor in rat brain synaptic cortical membranes after 60 mins by scintillation counting method
|
Rattus norvegicus
|
200.0
nM
|
|
Journal : J Med Chem
Title : Use of the 4-Hydroxytriazole Moiety as a Bioisosteric Tool in the Development of Ionotropic Glutamate Receptor Ligands.
Year : 2019
Volume : 62
Issue : 9
First Page : 4467
Last Page : 4482
Authors : Sainas S, Temperini P, Farnsworth JC, Yi F, Møllerud S, Jensen AA, Nielsen B, Passoni A, Kastrup JS, Hansen KB, Boschi D, Pickering DS, Clausen RP, Lolli ML.
Abstract : We report a series of glutamate and aspartate analogues designed using the hydroxy-1,2,3-triazole moiety as a bioisostere for the distal carboxylic acid. Compound 6b showed unprecedented selectivity among ( S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtypes, confirmed also by an unusual binding mode observed for the crystal structures in complex with the AMPA receptor GluA2 agonist-binding domain. Here, a methionine (Met729) was highly disordered compared to previous agonist-bound structures. This observation provides a possible explanation for the pharmacological profile. In the structure with 7a, an unusual organization of water molecules around the bioisostere arises compared to previous structures of ligands with other bioisosteres. Aspartate analogue 8 with the hydroxy-1,2,3-triazole moiety directly attached to glycine was unexpectedly able to activate both the glutamate and glycine agonist-binding sites of the N-methyl-d-aspartic acid receptor. These observations demonstrate novel features that arise when employing a hydroxytriazole moiety as a bioisostere for the distal carboxylic acid in glutamate receptor agonists.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
8.67
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
12.78
%
|
|
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.
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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
|
-0.04
%
|
|
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
|
-0.11
%
|
|
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
|
-0.11
%
|
|
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
|
-0.04
%
|
|
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.
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Displacement of [3H]CPP from rat brain cortical membranes NMDA receptor incubated for 30 mins by equilibrium binding assay
|
Rattus norvegicus
|
200.0
nM
|
|
Journal : J Nat Prod
Title : Diverse Aromatic Metabolites in the Solitary Tunicate Cnemidocarpa irene.
Year : 2020
Volume : 83
Issue : 10
First Page : 3156
Last Page : 3165
Authors : Miyako K,Yasuno Y,Shinada T,Fujita MJ,Sakai R
Abstract : Fourteen aromatic metabolites (6-19) were isolated from an aqueous extract of the solitary tunicate Cnemidocarpa irene collected in Hokkaido, Japan. The structures of the metabolites were determined based on the spectroscopic interpretations, including one- and two-dimensional NMR, mass spectra, UV, and circular dichroism data. The biopterin analogue 10 modulated the behavior of mice after intracerebroventricular injection and showed a weak affinity to ionotropic glutamate receptor subtypes. Analyses of fluorescent coelomic fluid of the tunicate revealed that pterin 12 was responsible for the fluorescence of the blood cells, while β-carbolines 1 and 3 were fluorescent compounds in the serum. The metabolic profiles in adults, juveniles, larvae, and eggs of the animal differed substantially, suggesting that the metabolism of the animal, especially biosynthesis of aromatic secondary metabolites, changes over different life stages.
|
Displacement of [3H]AMPA from rat brain cortical membranes AMPA receptor incubated for 30 mins by equilibrium binding assay
|
Rattus norvegicus
|
600.0
nM
|
|
Journal : J Nat Prod
Title : Diverse Aromatic Metabolites in the Solitary Tunicate Cnemidocarpa irene.
Year : 2020
Volume : 83
Issue : 10
First Page : 3156
Last Page : 3165
Authors : Miyako K,Yasuno Y,Shinada T,Fujita MJ,Sakai R
Abstract : Fourteen aromatic metabolites (6-19) were isolated from an aqueous extract of the solitary tunicate Cnemidocarpa irene collected in Hokkaido, Japan. The structures of the metabolites were determined based on the spectroscopic interpretations, including one- and two-dimensional NMR, mass spectra, UV, and circular dichroism data. The biopterin analogue 10 modulated the behavior of mice after intracerebroventricular injection and showed a weak affinity to ionotropic glutamate receptor subtypes. Analyses of fluorescent coelomic fluid of the tunicate revealed that pterin 12 was responsible for the fluorescence of the blood cells, while β-carbolines 1 and 3 were fluorescent compounds in the serum. The metabolic profiles in adults, juveniles, larvae, and eggs of the animal differed substantially, suggesting that the metabolism of the animal, especially biosynthesis of aromatic secondary metabolites, changes over different life stages.
|
Displacement of [3H]KA from rat brain cortical membranes Kainate receptor incubated for 30 mins by equilibrium binding assay
|
Rattus norvegicus
|
250.0
nM
|
|
Journal : J Nat Prod
Title : Diverse Aromatic Metabolites in the Solitary Tunicate Cnemidocarpa irene.
Year : 2020
Volume : 83
Issue : 10
First Page : 3156
Last Page : 3165
Authors : Miyako K,Yasuno Y,Shinada T,Fujita MJ,Sakai R
Abstract : Fourteen aromatic metabolites (6-19) were isolated from an aqueous extract of the solitary tunicate Cnemidocarpa irene collected in Hokkaido, Japan. The structures of the metabolites were determined based on the spectroscopic interpretations, including one- and two-dimensional NMR, mass spectra, UV, and circular dichroism data. The biopterin analogue 10 modulated the behavior of mice after intracerebroventricular injection and showed a weak affinity to ionotropic glutamate receptor subtypes. Analyses of fluorescent coelomic fluid of the tunicate revealed that pterin 12 was responsible for the fluorescence of the blood cells, while β-carbolines 1 and 3 were fluorescent compounds in the serum. The metabolic profiles in adults, juveniles, larvae, and eggs of the animal differed substantially, suggesting that the metabolism of the animal, especially biosynthesis of aromatic secondary metabolites, changes over different life stages.
