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Povl Krogsgaard-larsen - One of the best experts on this subject based on the ideXlab platform.
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Resolution, configurational assignment, and enantiopharmacology of 2‐amino‐3‐[3‐hydroxy‐5‐(2‐methyl‐2H‐tetrazol‐5‐yl)isoxazol‐4‐yl]propionic acid, a potent GluR3‐ and GluR4‐preferring AMPA Receptor Agonist
Chirality, 2020Co-Authors: Stine B Vogensen, Karla Frydenvang, Jan Egebjerg, Henrik Jensen, Tine B. Stensbøl, Benny Bang-andersen, Tommy N. Johansen, Povl Krogsgaard-larsenAbstract:We have previously shown that (RS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-tetrazol-5-yl)isoxazol -4-yl] propionic acid (2-Me-Tet-AMPA) is a selective Agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) Receptors, markedly more potent than AMPA itself, whereas the isomeric compound 1-Me-Tet-AMPA is essentially inactive. We here report the enantiopharmacology of 2-Me-Tet-AMPA in radioligand binding and cortical wedge electrophysiological assay systems, and using cloned AMPA (GluR1-4) and kainic acid (KA) (GluR5, 6, and KA2) Receptor subtypes expressed in Xenopus oocytes. 2-Me-Tet-AMPA was resolved using preparative chiral HPLC. Zwitterion (-)-2-Me-Tet-AMPA was assigned the (R)-configuration based on an X-ray crystallographic analysis supported by the elution order of (-)- and (+)-2-Me-Tet-AMPA using four different chiral HPLC columns and by circular dichroism spectra. None of the compounds tested showed detectable affinity for N-methyl-D-aspartic acid (NMDA) Receptor sites, and (R)-2-Me-Tet-AMPA was essentially inactive in all of the test systems used. Whereas (S)-2-Me-Tet-AMPA showed low affinity (IC(50) = 11 microM) in the [(3)H]KA binding assay, it was significantly more potent (IC(50) = 0.009 microM) than AMPA (IC(50) = 0.039 microM) in the [(3)H]AMPA binding assay, and in agreement with these findings, (S)-2-Me-Tet-AMPA (EC(50) = 0.11 microM) was markedly more potent than AMPA (EC(50) = 3.5 microM) in the electrophysiological cortical wedge model. In contrast to AMPA, which showed comparable potencies (EC(50) = 1.3-3.5 microM) at Receptors formed by the AMPA Receptor subunits (GluR1-4) in Xenopus oocytes, more potent effects and a substantially higher degree of subunit selectivity were observed for (S)-2-Me-Tet-AMPA: GluR1o (EC(50) = 0.16 microM), GluR1o/GluR2i (EC(50) = 0.12 microM), GluR3o (EC(50) = 0.014 microM) and GluR4o (EC(50) = 0.009 microM). At the KA-preferring Receptors GluR5 and GluR6/KA2, (S)-2-Me-Tet-AMPA showed much weaker Agonist effects (EC(50) = 8.7 and 15.3 microM, respectively). It is concluded that (S)-2-Me-Tet-AMPA is a subunit-selective and highly potent AMPA Receptor Agonist and a potentially useful tool for studies of physiological AMPA Receptor subtypes.
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Towards rational design of AMPA Receptor ligands: An integrated medicinal, computational, biostructural and molecular pharmacological approach
Pharmacochemistry Library, 2020Co-Authors: A. Hogner, Stine B Vogensen, Jeremy R Greenwood, Jan Egebjerg, Tine B. Stensbøl, Jette S. Kastrup, Eva H. Møller, Povl Krogsgaard-larsenAbstract:Publisher Summary This chapter outlines the development of a long-term academic medicinal chemistry project on glutamate Receptor ligands from a classical drug design project based on re-design of a naturally occurring amino acid “toxin,” ibotenic acid, into an integrated rational approach involving medicinal chemistry, X-ray crystallographic protein structural analysis, computational chemistry, and molecular pharmacology. The central excitatory neurotransmitter effects of (5)-glutamic acid [(5)-Glu] are mediated by three heterogeneous classes of ionotropic Receptors: N -methyl-D-aspartic acid (NMDA), 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), and kainic acid (KA) Receptors, and a number of subtypes of metabotropic Receptors. These or the distinct subtypes of these Receptors have been associated with certain neurologic and psychiatric diseases and are potential therapeutic targets in such diseases. In recent years, much interest has been directed toward the role of AMPA Receptors in the mechanisms associated with cognitive functions, and enhancement of AMPA Receptor functions has been shown to facilitate learning and memory. Although AMPA Receptor Agonists may not be used therapeutically because of potential neurotoxicity, these observations have focused interest on the molecular mechanisms of Receptor activation and, thus, on the structural basis of AMPA Receptor–Agonist interactions.
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Ionotropic excitatory amino acid Receptor ligands. Synthesis and pharmacology of a new amino acid AMPA antAgonist.
European Journal of Medicinal Chemistry, 2020Co-Authors: Ulf Madsen, Tine B. Stensbøl, Frank A. Sløk, Hans Bräuner-osborne, Hans-christian H Lützhøft, Miguel V. Poulsen, Lisbeth Eriksen, Povl Krogsgaard-larsenAbstract:Abstract We have previously described the potent and selective (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) Receptor Agonist, (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA), and the AMPA Receptor antAgonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA). Using these AMPA Receptor ligands as leads, a series of compounds have been developed as tools for further elucidation of the structural requirements for activation and blockade of AMPA Receptors. The synthesized compounds have been tested for activity at ionotropic excitatory amino acid (EAA) Receptors using Receptor binding and electrophysiological techniques, and for activity at metabotropic EAA Receptors using second messenger assays. Compounds 1 and 4 were essentially inactive. (RS)-2-Amino-3-[3-(2-carboxyethyl)-5-methyl-4-isoxazolyl]propionic acid (ACMP, 2), on the other hand, was shown to be a selective AMPA Receptor antAgonist (IC50 = 73 μM), more potent in electrophysiological experiments than AMOA (IC50 = 320 μM). The isomeric analogue of 2, compound 5, did not show AMPA antAgonist effects, but was a weak NMDA Receptor antAgonist (IC50 = 540 μM). Finally, compound 3, which is an isomer of ACPA, turned out to be a very weak NMDA antAgonist, and an AMPA Receptor Agonist approximately 1 000 times weaker than ACPA. None of the compounds showed Agonist or antAgonist effects at metabotropic EAA Receptors.
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Tetrazolyl isoxazole amino acids as ionotropic glutamate Receptor antAgonists: Synthesis, modelling and molecular pharmacology
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Bente Frølund, Jeremy R Greenwood, Birgitte Nielsen, Jan Egebjerg, Ulf Madsen, Tine B. Stensbøl, Hans Bräuner-osborne, Mai Marie Holm, Povl Krogsgaard-larsenAbstract:Abstract Two 3-(5-tetrazolylmethoxy) analogues, 1a and 1b , of ( RS )-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), a selective AMPA Receptor Agonist, and ( RS )-2-amino-3-(5- tert -butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), a GluR5-preferring Agonist, were synthesized. Compounds 1a and 1b were pharmacologically characterized in Receptor binding assays, and electrophysiologically on homomeric AMPA Receptors (GluR1-4), homomeric (GluR5 and GluR6) and heteromeric (GluR6/KA2) kainic acid Receptors, using two-electrode voltage-clamped Xenopus laevis oocytes expressing these Receptors. Both analogues proved to be antAgonists at all AMPA Receptor subtypes, showing potencies ( K b = 38–161 μM) similar to that of the AMPA Receptor antAgonist ( RS )-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA) ( K b = 43–76 μM). Furthermore, the AMOA analogue, 1a , blocked two kainic acid Receptor subtypes (GluR5 and GluR6/KA2), showing sevenfold preference for GluR6/KA2 ( K b = 19 μM). Unlike the iGluR antAgonist ( S )-2-amino-3-[5- tert -butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid [( S )-ATPO], the corresponding tetrazolyl analogue, 1b , lacks kainic acid Receptor effects. On the basis of docking to a crystal structure of the isolated extracellular ligand-binding core of the AMPA Receptor subunit GluR2 and a homology model of the kainic acid Receptor subunit GluR5, we were able to rationalize the observed structure–activity relationships.
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Synthesis and in vitro pharmacology at AMPA and kainate preferring glutamate Receptors of 4-heteroarylmethylidene glutamate analogues
Bioorganic & Medicinal Chemistry, 2003Co-Authors: Jon Valgeirsson, Birgitte Nielsen, Darryl S Pickering, Povl Krogsgaard-larsen, Hans Bräuner-osborne, Jeppe Kejser Christensen, Anders S. Kristensen, Christina H. Fischer, Elsebet Ø. Nielsen, Ulf MadsenAbstract:Abstract 2-Amino-3-[3-hydroxy-5-(2-thiazolyl)-4-isoxazolyl]propionic acid ( 1 ) is a potent AMPA Receptor Agonist with moderate affinity for native kainic acid (KA) Receptors, whereas ( S )- E -4-(2,2-dimethylpropylidene)glutamic acid ( 3 ) show high affinity for the GluR5 subtype of KA Receptors and much lower affinity for the GluR2 subtype of AMPA Receptors. As an attempt to develop new pharmacological tools for studies of GluR5 Receptors, ( S )- E -4-(2-thiazolylmethylene)glutamic acid ( 4a ) was designed as a structural hybrid between 1 and 3 . 4a was shown to be a potent GluR5 Agonist and a high affinity ligand and to indiscriminately bind to the AMPA Receptor subtypes GluR1–4 with lower affinities. Compounds 4b – h , in which the 2-thiazolyl substituent of 4a was replaced by other heterocyclic rings, which have previously been incorporated as 5-substituents in AMPA analogues, as exemplified by 1 were also synthesized. Compounds 4b – h were either inactive ( 4e , f ) or weaker than 4a as affinity ligands for GluR1–4 and GluR5 with relative potencies comparable with those of the corresponding AMPA analogues as AMPA Receptor Agonists. Compounds 4a – h may be useful tools for the progressing pharmacophore mapping of the GluR5 Agonist binding site.
Bjarke Ebert - One of the best experts on this subject based on the ideXlab platform.
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a tetrazolyl substituted subtype selective AMPA Receptor Agonist
Journal of Medicinal Chemistry, 2007Co-Authors: Stine B Vogensen, Karla Frydenvang, Jeremy R Greenwood, Giovanna Postorino, Birgitte Nielsen, Darryl S Pickering, Bjarke Ebert, Ulrik Bolcho, Jan Egebjerg, Michael GajhedeAbstract:Replacement of the methyl group of the AMPA Receptor Agonist 2-amino-3-[3-hydroxy-5-(2-methyl-2H-5-tetrazolyl)-4-isoxazolyl]propionic acid (2-Me-Tet-AMPA) with a benzyl group provided the first AMPA Receptor Agonist, compound 7, capable of discriminating GluR2−4 from GluR1 by its more than 10-fold preference for the former Receptor subtypes. An X-ray crystallographic analysis of this new analogue in complex with the GluR2-S1S2J construct shows that accommodation of the benzyl group creates a previously unobserved pocket in the Receptor, which may explain the remarkable pharmacological profile of compound 7.
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Resolution, absolute stereochemistry and molecular pharmacology of the enantiomers of ATPA.
European Journal of Pharmacology, 1999Co-Authors: Tine B. Stensbøl, Bjarke Ebert, Jan Egebjerg, Ulf Madsen, Tommy N. Johansen, Lars Borre, Povl Krogsgaard-larsenAbstract:Abstract ( RS )-2-Amino-3-(5- tert -butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), an analogue of ( RS )-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), has previously been shown to be a relatively weak AMPA Receptor Agonist and a very potent Agonist at the GluR5 subtype of kainic acid-preferring ( S )-glutamic acid (( S )-Glu) Receptors. We report here the separation of (+)- and (−)-ATPA, obtained at high enantiomeric purity (enantiomeric excess values of 99.8% and >99.8%, respectively) using chiral chromatography, and the unequivocal assignment of the stereochemistry of ( S )-(+)-ATPA and ( R )-(−)-ATPA. ( S )- and ( R )-ATPA were characterized in Receptor binding studies using rat brain membranes, and electrophysiologically using the rat cortical wedge preparation and cloned AMPA-preferring (GluR1, GluR3, and GluR4) and kainic acid-preferring (GluR5, GluR6, and GluR6+ KA2) Receptors expressed in Xenopus oocytes. In the cortical wedge, ( S )-ATPA showed AMPA Receptor Agonist effects (EC 50 =23 μM) approximately twice as potent as those of ATPA. ( R )-ATPA antagonized depolarizations induced by AMPA ( K i =253 μM) and by ( S )-ATPA ( K i =376 μM), and ( R )-ATPA antagonized the biphasic depolarizing effects induced by kainic acid ( K i =301 μM and 1115 μM). At cloned AMPA Receptors, ( S )-ATPA showed Agonist effects at GluR3 and GluR4 with EC 50 values of approximately 8 μM and at GluR1 (EC 50 =22 μM), producing maximal steady state currents only 5.4–33% of those evoked by kainic acid. ( R )-ATPA antagonized currents evoked by kainic acid at cloned AMPA Receptor subtypes with K i values of 33–75 μM. ( S )-ATPA produced potent Agonist effects at GluR5 (EC 50 =0.48 μM). Due to desensitization of GluR5 Receptors, which could not be fully prevented by treatment with concanavalin A, ( S )-ATPA-induced Agonist effects were normalized to those of kainic acid. Under these circumstances, maximal currents produced by ( S )-ATPA and kainic acid were not significantly different. ( R )-ATPA did not attenuate currents produced by kainic acid at GluR5, and neither ( S )- nor ( R )-ATPA showed significant effects at GluR6. ( S )-ATPA as well as AMPA showed weak Agonist effects at heteromeric GluR6+KA2 Receptors, whereas ( R )-ATPA was inactive. Thus, ( S )- and ( R )-ATPA may be useful tools for mechanistic studies of ionotropic non-NMDA ( S )-Glu Receptors, and lead structures for the design of new subtype-selective ligands for such Receptors.
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Excitatory amino acid Receptor ligands : Resolution, absolute stereochemistry, and enantiopharmacology of 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid
Journal of Medicinal Chemistry, 1998Co-Authors: Tommy N. Johansen, Bjarke Ebert, Ulf Madsen, Povl Krogsgaard-larsen, Hans Bräuner-osborne, Michael Didriksen, Karina Krøjer Søby, Inge T. Christensen, Lotte BrehmAbstract:(RS)-2-Amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid (Bu-HIBO, 6) has previously been shown to be an Agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) Receptors and an inhibitor of CaCl2-dependent [3H]-(S)-glutamic acid binding (J. Med. Chem. 1992, 35, 3512-3519). To elucidate the pharmacological significance of this latter binding affinity, which is also shown by quisqualic acid (3) but not by AMPA, we have now resolved Bu-HIBO via diastereomeric salt formation using the diprotected Bu-HIBO derivative 11 and the enantiomers of 1-phenylethylamine (PEA). The absolute stereochemistry of (S)-Bu-HIBO (7) (ee = 99.0%) and (R)-Bu-HIBO (8) (ee > 99.6%) were established by an X-ray crystallographic analysis of compound 15, a salt of (R)-PEA, and diprotected 8. Circular dichroism spectra of 7 and 8 were recorded. Whereas 7 (IC50 = 0.64 microM) and 8 (IC50 = 0.57 microM) were equipotent as inhibitors of CaCl2-dependent [3H]-(S)-glutamic acid binding, neither enantiomer showed significant affinity for the synaptosomal (S)-glutamic acid uptake system(s). AMPA Receptor affinity (IC50 = 0.48 microM) and agonism (EC50 = 17 microM) were shown to reside exclusively in the S-enantiomer, 7. Compounds 7 and 8 did not interact detectably with kainic acid or N-methyl-D-aspartic acid (NMDA) Receptor sites. Neither 7 nor 8 affected the function of the metabotropic (S)-glutamic acid Receptors mGlu2 and mGlu4a, expressed in CHO cells. Compound 8 was shown also to be inactive at mGlu1 alpha, whereas 7 was determined to be a moderately potent antAgonist at mGlu1 alpha (Ki = 110 microM) and mGlu5a (Ki = 97 microM). Using the rat cortical wedge preparation, the AMPA Receptor Agonist effect of 7 was markedly potentiated by coadministration of 8 at 21 degrees C, but not at 2-4 degrees C. These observations together indicate that the potentiation of the AMPA Receptor agonism of 7 by 8 is not mediated by metabotropic (S)-glutamate Receptors but rather by the CaCl2-dependent (S)-glutamic acid binding system, which shows the characteristics of a transport mechanism. After intravenous administration in mice, 7 (ED50 = 44 mumol/kg) was slightly more potent than AMPA (1) (ED50 = 55 mumol/kg) and twice as potent as Bu-HIBO (6) (ED50 = 94 mumol/kg) as a convulsant, whereas 8 was inactive. After subcutaneous administration in mice, Bu-HIBO (ED50 = 110 mumol/kg) was twice as potent as AMPA (ED50 = 220 mumol/kg) as a convulsant. Since 7 and Bu-HIBO (EC50 = 37 microM) are much weaker than AMPA (EC50 = 3.5 microM) as AMPA Receptor Agonists in vitro, the presence of a butyl group in the molecules of Bu-HIBO and 7 seems to facilitate the penetration of these compounds through the blood-brain barrier.
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Bioisosterically modified dipeptide excitatory amino acid Receptor antAgonists containing 3-oxygenated isothiazole ring systems
Bioorganic & Medicinal Chemistry, 1997Co-Authors: Lisa Matzen, Bjarke Ebert, Tine B. Stensbøl, Bente Frølund, Jerzy W. Jaroszewski, Povl Krogsgaard-larsenAbstract:Abstract The AMPA Receptor Agonist Thio-AMPA, the 3-isothiazolol analogue of AMPA was converted into the selective NMDA antAgonist, 2 , in which a 3-isothiazolone unit is a bioisosteric analogue of the peptide bond of the NMDA antAgonist, γ -( R )-Glu-Gly. The isomeric 3-oxygenated isothiazole amino acid, 3 , and the corresponding isothiazole phosphono amino acid 4 were also synthesized, and were shown to be selective AMPA Receptor antAgonists. Compound 1 , in which the peptide bond of γ -( R )-Glu-Gly is replaced by an ester group, was synthesized and shown to be unstable in the test buffer system.
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AMPA Receptor Agonists: resolution, configurational assignment, and pharmacology of (+)-(S)- and (-)-(R)-2-amino-3-[3-hydroxy-5-(2-pyridyl)-isoxazol-4-yl]-propionic acid (2-Py-AMPA).
Chirality, 1997Co-Authors: Tommy N. Johansen, Bjarke Ebert, Erik Falch, Povl Krogsgaard-larsenAbstract:We have previously shown that whereas (RS)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA) shows the characteristics of a partial Agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) Receptors, (S)-APPA is a full AMPA Receptor Agonist and (R)-APPA a weak competitive AMPA Receptor antAgonist. This observation led us to introduce the new pharmacological concept, functional partial agonism. Recently we have shown that the 2-pyridyl analogue of APPA, (RS)-2-amino-3-[3-hydroxy-5-(2-pyridyl)isoxazol-4-yl]propionic acid (2-Py-AMPA), is a potent and apparently full AMPA Receptor Agonist, and this compound has now been resolved into (+)- and (-)-2-Py-AMPA (ee > or = 99.0%) by chiral HPLC using a Chirobiotic T column. The absolute stereochemistry of the enantiomers of APPA has previously been established by X-ray analysis, and on the basis of comparative studies of the circular dichroism spectra of the enantiomers of APPA and 2-Py-AMPA, (+)- and (-)-2-Py-AMPA were assigned the (S)- and (R)-configuration, respectively. In a series of Receptor binding studies, neither enantiomer of 2-Py-AMPA showed detectable affinity for kainic acid Receptor sites or different sites at the N-methyl-D-aspartic acid (NMDA) Receptor complex. (+)-(S)-2-Py-AMPA was an effective inhibitor of [3H]AMPA binding (IC50 = 0.19 +/- 0.06 microM) and a potent AMPA Receptor Agonist in the rat cortical wedge preparation (EC50 = 4.5 +/- 0.3 microM) comparable with AMPA (IC50 = 0.040 +/- 0.01 microM; EC50 = 3.5 +/- 0.2 microM), but much more potent than (+)-(S)-APPA (IC50 = 5.5 +/- 2.2 microM; EC50 = 230 +/- 12 microM). Like (-)-(R)-APPA (IC50 > 100 microM), (-)-(R)-2-Py-AMPA (IC50 > 100 microM) did not significantly affect [3H]AMPA binding, and both compounds were weak AMPA Receptor antAgonists (Ki = 270 +/- 50 and 290 +/- 20 microM, respectively).
Ulf Madsen - One of the best experts on this subject based on the ideXlab platform.
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Ionotropic excitatory amino acid Receptor ligands. Synthesis and pharmacology of a new amino acid AMPA antAgonist.
European Journal of Medicinal Chemistry, 2020Co-Authors: Ulf Madsen, Tine B. Stensbøl, Frank A. Sløk, Hans Bräuner-osborne, Hans-christian H Lützhøft, Miguel V. Poulsen, Lisbeth Eriksen, Povl Krogsgaard-larsenAbstract:Abstract We have previously described the potent and selective (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) Receptor Agonist, (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA), and the AMPA Receptor antAgonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA). Using these AMPA Receptor ligands as leads, a series of compounds have been developed as tools for further elucidation of the structural requirements for activation and blockade of AMPA Receptors. The synthesized compounds have been tested for activity at ionotropic excitatory amino acid (EAA) Receptors using Receptor binding and electrophysiological techniques, and for activity at metabotropic EAA Receptors using second messenger assays. Compounds 1 and 4 were essentially inactive. (RS)-2-Amino-3-[3-(2-carboxyethyl)-5-methyl-4-isoxazolyl]propionic acid (ACMP, 2), on the other hand, was shown to be a selective AMPA Receptor antAgonist (IC50 = 73 μM), more potent in electrophysiological experiments than AMOA (IC50 = 320 μM). The isomeric analogue of 2, compound 5, did not show AMPA antAgonist effects, but was a weak NMDA Receptor antAgonist (IC50 = 540 μM). Finally, compound 3, which is an isomer of ACPA, turned out to be a very weak NMDA antAgonist, and an AMPA Receptor Agonist approximately 1 000 times weaker than ACPA. None of the compounds showed Agonist or antAgonist effects at metabotropic EAA Receptors.
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Tetrazolyl isoxazole amino acids as ionotropic glutamate Receptor antAgonists: Synthesis, modelling and molecular pharmacology
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Bente Frølund, Jeremy R Greenwood, Birgitte Nielsen, Jan Egebjerg, Ulf Madsen, Tine B. Stensbøl, Hans Bräuner-osborne, Mai Marie Holm, Povl Krogsgaard-larsenAbstract:Abstract Two 3-(5-tetrazolylmethoxy) analogues, 1a and 1b , of ( RS )-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), a selective AMPA Receptor Agonist, and ( RS )-2-amino-3-(5- tert -butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), a GluR5-preferring Agonist, were synthesized. Compounds 1a and 1b were pharmacologically characterized in Receptor binding assays, and electrophysiologically on homomeric AMPA Receptors (GluR1-4), homomeric (GluR5 and GluR6) and heteromeric (GluR6/KA2) kainic acid Receptors, using two-electrode voltage-clamped Xenopus laevis oocytes expressing these Receptors. Both analogues proved to be antAgonists at all AMPA Receptor subtypes, showing potencies ( K b = 38–161 μM) similar to that of the AMPA Receptor antAgonist ( RS )-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA) ( K b = 43–76 μM). Furthermore, the AMOA analogue, 1a , blocked two kainic acid Receptor subtypes (GluR5 and GluR6/KA2), showing sevenfold preference for GluR6/KA2 ( K b = 19 μM). Unlike the iGluR antAgonist ( S )-2-amino-3-[5- tert -butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid [( S )-ATPO], the corresponding tetrazolyl analogue, 1b , lacks kainic acid Receptor effects. On the basis of docking to a crystal structure of the isolated extracellular ligand-binding core of the AMPA Receptor subunit GluR2 and a homology model of the kainic acid Receptor subunit GluR5, we were able to rationalize the observed structure–activity relationships.
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Synthesis and in vitro pharmacology at AMPA and kainate preferring glutamate Receptors of 4-heteroarylmethylidene glutamate analogues
Bioorganic & Medicinal Chemistry, 2003Co-Authors: Jon Valgeirsson, Birgitte Nielsen, Darryl S Pickering, Povl Krogsgaard-larsen, Hans Bräuner-osborne, Jeppe Kejser Christensen, Anders S. Kristensen, Christina H. Fischer, Elsebet Ø. Nielsen, Ulf MadsenAbstract:Abstract 2-Amino-3-[3-hydroxy-5-(2-thiazolyl)-4-isoxazolyl]propionic acid ( 1 ) is a potent AMPA Receptor Agonist with moderate affinity for native kainic acid (KA) Receptors, whereas ( S )- E -4-(2,2-dimethylpropylidene)glutamic acid ( 3 ) show high affinity for the GluR5 subtype of KA Receptors and much lower affinity for the GluR2 subtype of AMPA Receptors. As an attempt to develop new pharmacological tools for studies of GluR5 Receptors, ( S )- E -4-(2-thiazolylmethylene)glutamic acid ( 4a ) was designed as a structural hybrid between 1 and 3 . 4a was shown to be a potent GluR5 Agonist and a high affinity ligand and to indiscriminately bind to the AMPA Receptor subtypes GluR1–4 with lower affinities. Compounds 4b – h , in which the 2-thiazolyl substituent of 4a was replaced by other heterocyclic rings, which have previously been incorporated as 5-substituents in AMPA analogues, as exemplified by 1 were also synthesized. Compounds 4b – h were either inactive ( 4e , f ) or weaker than 4a as affinity ligands for GluR1–4 and GluR5 with relative potencies comparable with those of the corresponding AMPA analogues as AMPA Receptor Agonists. Compounds 4a – h may be useful tools for the progressing pharmacophore mapping of the GluR5 Agonist binding site.
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Glutamate Receptor ligands: synthesis, stereochemistry, and enantiopharmacology of methylated 2-aminoadipic acid analogs.
Chirality, 2002Co-Authors: Mette Guldbrandt, Karla Frydenvang, Birgitte Nielsen, Tine B. Stensbøl, Tommy N. Johansen, Povl Krogsgaard-larsen, Hans Bräuner-osborne, Rolf Karla, Flavio Santi, Ulf MadsenAbstract:Homologation and substitution on the carbon backbone of (S)-glutamic acid [(S)-Glu, 1], as well as absolute stereochemistry, are structural parameters of key importance for the pharmacological profile of (S)-Glu Receptor ligands. We describe a series of methyl-substituted 2-aminoadipic acid (AA) analogs, and the synthesis, stereochemistry, and enantiopharmacology of 3-methyl-AA (4a–d), 4-methyl-AA (5a–d), 5-methyl-AA (6a–d), and (E)-Δ4-5-methyl-AA (7a and 7b) are reported. The compounds were resolved using chiral HPLC and the configurational assignments of the enantiomers were based on X-ray crystallographic analyses, chemical correlation, and CD spectral analyses. The effects of the individual stereoisomers at ionotropic and metabotropic (S)-Glu Receptors (iGluRs and mGluRs) were characterized. Compounds with S-configuration at the α-carbon generally showed mGluR2 Agonist activity of similar or slightly lower potencies than (S)-AA [e.g., EC50 = 76 μM for (2S,4S)-4-methyl-AA (5a) as compared to EC50 = 35 μM for (S)-AA]. The position of the methyl substituent had a profound effect on the observed pharmacology, whereas the absolute stereochemistry at the methylated carbon atom had a very limited effect on pharmacology. Structure–activity relationships at iGluRs in the rat cortical wedge preparation showed a complex pattern, some compounds being NMDA Receptor Agonists [e.g., EC50 =110 μM for (2S,5RS)-5-methyl-AA (6a,b)] and some compounds showing NMDA Receptor antAgonist effects [e.g., IC50 = 300 μM for (2R,4S)-4-methyl-AA (5d)]. The two unsaturated analogs (S)- (7a) and (R)-(E)-Δ4-5-methyl-AA (7b) turned out to be a weak AMPA Receptor Agonist and a weak mixed NMDA/AMPA Receptor antAgonist, respectively. Chirality 14:351–363, 2002. © 2002 Wiley-Liss, Inc.
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Novel 1-hydroxyazole bioisosteres of glutamic acid. Synthesis, protolytic properties, and pharmacology.
Journal of Medicinal Chemistry, 2002Co-Authors: Tine B. Stensbøl, Jeremy R Greenwood, Hans Bräuner-osborne, Mette Brunsgaard Hermit, Peter Uhlmann, Sandrine Morel, Birgitte Langer Eriksen, Jakob Felding, Hasse Kromann, Ulf MadsenAbstract:A number of 1-hydroxyazole derivatives were synthesized as bioisosteres of (S)-glutamic acid (Glu) and as analogues of the AMPA Receptor Agonist (R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA, 3b). All compounds were subjected to in vitro pharmacological studies, including a series of Glu Receptor binding assays, uptake studies on native as well as cloned Glu uptake systems, and the electrophysiological rat cortical slice model. Compounds 7a,b, analogues of AMPA bearing a 1-hydroxy-5-pyrazolyl moiety as the distal carboxylic functionality, showed only moderate affinity for [ 3 H]AMPA Receptor binding sites (IC 50 = 2.7 ± 0.4 μM and IC 50 = 2.6 ± 0.6 μM, respectively), correlating with electrophysiological data from the rat cortical wedge model (EC 50 = 280 ± 48 μM and EC 50 = 586 ± 41 μM, respectively). 1-Hydroxy-1,2,3-triazol-5-yl analogues of AMPA, compounds 8a,b, showed high affinity for [ 3 H]-AMPA Receptor binding sites (IC 50 = 0.15 ± 0.03 μM and IC 50 = 0.13 ± 0.02 μM, respectively). Electrophysiological data showed that compound 8a was devoid of activity in the rat cortical wedge model (EC 50 > 1000 μM), whereas the corresponding 4-methyl analogue 8b was a potent AMPA Receptor Agonist (EC 50 = 15 ± 2 μM). In accordance with this disparity, compound 8a was found to inhibit synaptosomal [ 3 H]D-aspartic acid uptake (IC 50 = 93 ± 25 μM), as well as excitatory amino acid transporters (EAATs) EAAT1 (IC 50 = 100 ± 30 μM) and EAAT2 (IC 50 = 300 ± 80 μM). By contrast, compound 8b showed no appreciable affinity for Glu uptake sites, neither synaptosomal nor cloned. Compounds 9a-c and 10a,b, possessing 1-hydroxyimidazole as the terminal acidic function, were devoid of activity in all of the systems tested. Protolytic properties of compounds 7a,b, 8b, and 9b were determined by titration, and a correlation between the pK a values and the activity at AMPA Receptors was apparent. Optimized structures of all the synthesized ligands were fitted to the known crystal structure of an AMPA-GluR2 construct. Where substantial reduction or abolition of affinity at AMPA Receptors was observed, this could be rationalized on the basis of the ability of the ligand to fit the construct. The results presented in this article point to the utility of 1-hydroxypyrazole and 1,2,3-hydroxytriazole as bioisosteres of carboxylic acids at Glu Receptors and transporters. None of the compounds showed significant activity at metabotropic Glu Receptors.
Povl Krogsgaardlarsen - One of the best experts on this subject based on the ideXlab platform.
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excitatory amino acids synthesis of rs 2 amino 3 5 cyclopropyl 3 hydroxyisoxazol 4 yl propionic acid a new potent and specific AMPA Receptor Agonist
Journal of The Chemical Society-perkin Transactions 1, 1995Co-Authors: Niels Skjaerbaek, Bjarke Ebert, Erik Falch, Lotte Brehm, Povl KrogsgaardlarsenAbstract:The synthesis of (RS)-2-amino-3-(5-cyclopropyl-3-hydroxyisoxazol-4-yl)propionic acid 6, an analogue of the AMPA Receptor Agonist (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic acid, AMPA, 3 is described. Compound 6 has been studied in vitro in radioligand binding and electrophysiological test systems and shown to be a specific AMPA Receptor Agonist equipotent with AMPA. The synthesis of 6 was based on 5-cyclopropyl-3-hydroxyisoxazole 8, which was converted into the intermediate 4-bromomethyl-5-(3-bromopropyl)-2-methoxymethyl-2,3-dihydroisoxazol-3-one 9 by opening of the cyclopropane ring. Based on 1H and 13C NMR data, this conversion has been shown to proceed stepwise, the progression of the different steps being dependent on the concentration of the hydrobromic acid medium, reaction time, and temperature. An acetamidomalonate group has been regiospecifically substituted for the allylic bromine atom of 9 to give 10, and treatment of 10 with sodium hydride gave compound 11 containing a cyclopropyl group, reformed by cyclization of the 3-bromopropyl substituent of 10. Compound 11 has been fully deprotected by treatment with aqueous trifluoroacetic acid to give 6.
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resolution absolute stereochemistry and pharmacology of the s and r isomers of the apparent partial AMPA Receptor Agonist r s 2 amino 3 3 hydroxy 5 phenylisoxazol 4 yl propionic acid r s appa
Journal of Medicinal Chemistry, 1994Co-Authors: Bjarke Ebert, Lotte Brehm, Sibylle Moltzen Lenz, Jan J. Hansen, Klaus Peter Bogeso, Peter Bregnedal, Kristen Frederiksen, Povl KrogsgaardlarsenAbstract:(R,S)-2-Amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid ((R,S)-APPA) is the only partial Agonist at the (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) subtype of excitatory amino acid Receptors so far described. In light of the pharmacological interest in partial Agonists, we have now accomplished the resolution of (R,S)-APPA. (S)-(+)-APPA (5) and (R)-(-)-APPA (6) were obtained in high enantiomeric purity using (R)-(+)- and (S)-(-)-1-phenylethylamine, respectively, as resolving agents. The absolute stereochemistry of 6 was established by X-ray analysis of 6-HCl-0.25H 2 O. Compounds 5 and 6 were tested electropharmacologically using the rat cortical wedge preparation and in Receptor-binding assays using [ 3 H]-AMPA, [ 3 H]kainic acid, and the N-methyl-D-aspartic acid (NMDA) Receptor ligands [ 3 H]CPP, [ 3 H]MK-801, and [ 3 H]glycine. Whereas 6 did not significantly affect the binding of any of these ligands (IC 50 > 100 μM), compound 5 revealed affinity for only the [ 3 H]AMPA-binding site (IC 50 =6 μM). In electropharmacological tests, 5 showed full AMPA Receptor agonism (EC 50 =230 μM). This effect of 5 was insensitive to the NMDA antAgonist CPP but was inhibited competitively by the non-NMDA antAgonist NBQX (pK i =6.30). Compound 6, on the other hand, turned out to be a non-NMDA Receptor antAgonist, inhibiting competitively depolarizations induced by AMPA (pK i =3.54), kainic acid (pK i =3.07) and 5 (pK i =3.57)
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synthesis and pharmacology of rs 2 amino 3 3 hydroxy 5 trifluoromethyl 4 isoxazolyl propionic acid a potent AMPA Receptor Agonist
European Journal of Medicinal Chemistry, 1992Co-Authors: Ulf Madsen, Bjarke Ebert, Povl Krogsgaardlarsen, Erik H F WongAbstract:Abstract Three isoxazole bioisosteres of glutamic acid derived from the specific AMPA Receptor Agonist (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) were synthesized and tested electrophysiologically and in different Receptor binding systems. (RS)-2-Amino-3-(3-hydroxy-5-trifluoromethyl-4-isoxazolyl)propionic acid (trifluoro-AMPA, 8) showed more potent Agonist activity (EC50 2.3 μM) and lower affinity (IC50 0.08 μM) for AMPA Receptors than AMPA itself (EC50 3.5 μM and IC50 0.04 μM, respectively). Like AMPA, trifluoro-AMPA (8) did not bind significantly to N-methyl- d -aspartic acid (NMDA) Receptor sites, but trifluoro-AMPA (8) was more potent as an inhibitor of [3H]kainic acid ([3H]KAIN) binding (IC50 7.1 μM) than AMPA (IC50 32 μM). (RS)-2-Amino-3-(3-chloro-5-methyl-4-isoxazolyl)propionic acid (14), the 3-chloro analogue of AMPA, and the isomeric compound (RS)-2-amino-3-(3-chloro-4-methyl-5-isoxazolyl)propionic acid (15), did not show significant neuroexcitatory effects at or affinities for AMPA, NMDA, or KAIN Receptor sites.
Tine B. Stensbøl - One of the best experts on this subject based on the ideXlab platform.
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Resolution, configurational assignment, and enantiopharmacology of 2‐amino‐3‐[3‐hydroxy‐5‐(2‐methyl‐2H‐tetrazol‐5‐yl)isoxazol‐4‐yl]propionic acid, a potent GluR3‐ and GluR4‐preferring AMPA Receptor Agonist
Chirality, 2020Co-Authors: Stine B Vogensen, Karla Frydenvang, Jan Egebjerg, Henrik Jensen, Tine B. Stensbøl, Benny Bang-andersen, Tommy N. Johansen, Povl Krogsgaard-larsenAbstract:We have previously shown that (RS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-tetrazol-5-yl)isoxazol -4-yl] propionic acid (2-Me-Tet-AMPA) is a selective Agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) Receptors, markedly more potent than AMPA itself, whereas the isomeric compound 1-Me-Tet-AMPA is essentially inactive. We here report the enantiopharmacology of 2-Me-Tet-AMPA in radioligand binding and cortical wedge electrophysiological assay systems, and using cloned AMPA (GluR1-4) and kainic acid (KA) (GluR5, 6, and KA2) Receptor subtypes expressed in Xenopus oocytes. 2-Me-Tet-AMPA was resolved using preparative chiral HPLC. Zwitterion (-)-2-Me-Tet-AMPA was assigned the (R)-configuration based on an X-ray crystallographic analysis supported by the elution order of (-)- and (+)-2-Me-Tet-AMPA using four different chiral HPLC columns and by circular dichroism spectra. None of the compounds tested showed detectable affinity for N-methyl-D-aspartic acid (NMDA) Receptor sites, and (R)-2-Me-Tet-AMPA was essentially inactive in all of the test systems used. Whereas (S)-2-Me-Tet-AMPA showed low affinity (IC(50) = 11 microM) in the [(3)H]KA binding assay, it was significantly more potent (IC(50) = 0.009 microM) than AMPA (IC(50) = 0.039 microM) in the [(3)H]AMPA binding assay, and in agreement with these findings, (S)-2-Me-Tet-AMPA (EC(50) = 0.11 microM) was markedly more potent than AMPA (EC(50) = 3.5 microM) in the electrophysiological cortical wedge model. In contrast to AMPA, which showed comparable potencies (EC(50) = 1.3-3.5 microM) at Receptors formed by the AMPA Receptor subunits (GluR1-4) in Xenopus oocytes, more potent effects and a substantially higher degree of subunit selectivity were observed for (S)-2-Me-Tet-AMPA: GluR1o (EC(50) = 0.16 microM), GluR1o/GluR2i (EC(50) = 0.12 microM), GluR3o (EC(50) = 0.014 microM) and GluR4o (EC(50) = 0.009 microM). At the KA-preferring Receptors GluR5 and GluR6/KA2, (S)-2-Me-Tet-AMPA showed much weaker Agonist effects (EC(50) = 8.7 and 15.3 microM, respectively). It is concluded that (S)-2-Me-Tet-AMPA is a subunit-selective and highly potent AMPA Receptor Agonist and a potentially useful tool for studies of physiological AMPA Receptor subtypes.
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Ionotropic excitatory amino acid Receptor ligands. Synthesis and pharmacology of a new amino acid AMPA antAgonist.
European Journal of Medicinal Chemistry, 2020Co-Authors: Ulf Madsen, Tine B. Stensbøl, Frank A. Sløk, Hans Bräuner-osborne, Hans-christian H Lützhøft, Miguel V. Poulsen, Lisbeth Eriksen, Povl Krogsgaard-larsenAbstract:Abstract We have previously described the potent and selective (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) Receptor Agonist, (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA), and the AMPA Receptor antAgonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA). Using these AMPA Receptor ligands as leads, a series of compounds have been developed as tools for further elucidation of the structural requirements for activation and blockade of AMPA Receptors. The synthesized compounds have been tested for activity at ionotropic excitatory amino acid (EAA) Receptors using Receptor binding and electrophysiological techniques, and for activity at metabotropic EAA Receptors using second messenger assays. Compounds 1 and 4 were essentially inactive. (RS)-2-Amino-3-[3-(2-carboxyethyl)-5-methyl-4-isoxazolyl]propionic acid (ACMP, 2), on the other hand, was shown to be a selective AMPA Receptor antAgonist (IC50 = 73 μM), more potent in electrophysiological experiments than AMOA (IC50 = 320 μM). The isomeric analogue of 2, compound 5, did not show AMPA antAgonist effects, but was a weak NMDA Receptor antAgonist (IC50 = 540 μM). Finally, compound 3, which is an isomer of ACPA, turned out to be a very weak NMDA antAgonist, and an AMPA Receptor Agonist approximately 1 000 times weaker than ACPA. None of the compounds showed Agonist or antAgonist effects at metabotropic EAA Receptors.
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Towards rational design of AMPA Receptor ligands: An integrated medicinal, computational, biostructural and molecular pharmacological approach
Pharmacochemistry Library, 2020Co-Authors: A. Hogner, Stine B Vogensen, Jeremy R Greenwood, Jan Egebjerg, Tine B. Stensbøl, Jette S. Kastrup, Eva H. Møller, Povl Krogsgaard-larsenAbstract:Publisher Summary This chapter outlines the development of a long-term academic medicinal chemistry project on glutamate Receptor ligands from a classical drug design project based on re-design of a naturally occurring amino acid “toxin,” ibotenic acid, into an integrated rational approach involving medicinal chemistry, X-ray crystallographic protein structural analysis, computational chemistry, and molecular pharmacology. The central excitatory neurotransmitter effects of (5)-glutamic acid [(5)-Glu] are mediated by three heterogeneous classes of ionotropic Receptors: N -methyl-D-aspartic acid (NMDA), 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), and kainic acid (KA) Receptors, and a number of subtypes of metabotropic Receptors. These or the distinct subtypes of these Receptors have been associated with certain neurologic and psychiatric diseases and are potential therapeutic targets in such diseases. In recent years, much interest has been directed toward the role of AMPA Receptors in the mechanisms associated with cognitive functions, and enhancement of AMPA Receptor functions has been shown to facilitate learning and memory. Although AMPA Receptor Agonists may not be used therapeutically because of potential neurotoxicity, these observations have focused interest on the molecular mechanisms of Receptor activation and, thus, on the structural basis of AMPA Receptor–Agonist interactions.
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Tetrazolyl isoxazole amino acids as ionotropic glutamate Receptor antAgonists: Synthesis, modelling and molecular pharmacology
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Bente Frølund, Jeremy R Greenwood, Birgitte Nielsen, Jan Egebjerg, Ulf Madsen, Tine B. Stensbøl, Hans Bräuner-osborne, Mai Marie Holm, Povl Krogsgaard-larsenAbstract:Abstract Two 3-(5-tetrazolylmethoxy) analogues, 1a and 1b , of ( RS )-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), a selective AMPA Receptor Agonist, and ( RS )-2-amino-3-(5- tert -butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), a GluR5-preferring Agonist, were synthesized. Compounds 1a and 1b were pharmacologically characterized in Receptor binding assays, and electrophysiologically on homomeric AMPA Receptors (GluR1-4), homomeric (GluR5 and GluR6) and heteromeric (GluR6/KA2) kainic acid Receptors, using two-electrode voltage-clamped Xenopus laevis oocytes expressing these Receptors. Both analogues proved to be antAgonists at all AMPA Receptor subtypes, showing potencies ( K b = 38–161 μM) similar to that of the AMPA Receptor antAgonist ( RS )-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA) ( K b = 43–76 μM). Furthermore, the AMOA analogue, 1a , blocked two kainic acid Receptor subtypes (GluR5 and GluR6/KA2), showing sevenfold preference for GluR6/KA2 ( K b = 19 μM). Unlike the iGluR antAgonist ( S )-2-amino-3-[5- tert -butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid [( S )-ATPO], the corresponding tetrazolyl analogue, 1b , lacks kainic acid Receptor effects. On the basis of docking to a crystal structure of the isolated extracellular ligand-binding core of the AMPA Receptor subunit GluR2 and a homology model of the kainic acid Receptor subunit GluR5, we were able to rationalize the observed structure–activity relationships.
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Selective Agonists at Group II Metabotropic Glutamate Receptors: Synthesis, Stereochemistry, and Molecular Pharmacology of (S)- and (R)-2-Amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric Acid
Journal of Medicinal Chemistry, 2002Co-Authors: Rasmus P. Clausen, Jeremy R Greenwood, Tine B. Stensbøl, Hans Bräuner-osborne, Mette Brunsgaard Hermit, And Birgitte Nielsen, Povl Krogsgaard-larsenAbstract:Homologation of analogues of the central excitatory neurotransmitter glutamic acid (Glu), in which the distal carboxy group has been bioisosterically replaced by acidic heterocyclic units, has previously provided subtype selective ligands for metabotropic Glu Receptors (mGluRs). The (S)-form of the 1,2,5-thiadiazol-3-ol Glu analogue, 2-amino-3-(4-hydroxy[1,2,5]thiadiazol-3-yl)propionic acid (TDPA, 6), is an 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) Receptor Agonist, which in addition stereospecifically activates group I mGluRs. We have now synthesized the (S)- and (R)-forms of 2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid (homo-TDPA, 7) and shown that whereas neither enantiomer interacts with AMPA Receptors, (S)- and (R)-7 appear to be selective and equipotent Agonists at group II mGluRs as represented by the mGluR2 subtype. The activities of (S)- and (R)-7 are rationalized by conformational analysis, comparison with the potent and specific group II mGluR Agonist (−)-LY379...
