AMPA Receptor Agonist - Explore the Science & Experts | ideXlab

Scan Science and Technology

Contact Leading Edge Experts & Companies

AMPA Receptor Agonist

The Experts below are selected from a list of 201 Experts worldwide ranked by ideXlab platform

Povl Krogsgaard-larsen – 1st expert on this subject based on the ideXlab platform

  • 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, 2020
    Co-Authors: Stine B Vogensen, Karla Frydenvang, Jan Egebjerg, Henrik Jensen, Tine B. Stensbøl, Benny Bang-andersen, Tommy N. Johansen, Povl Krogsgaard-larsen

    Abstract:

    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.

  • Ionotropic excitatory amino acid Receptor ligands. Synthesis and pharmacology of a new amino acid AMPA antAgonist.
    European Journal of Medicinal Chemistry, 2020
    Co-Authors: Ulf Madsen, Tine B. Stensbøl, Frank A. Sløk, Hans Bräuner-osborne, Hans-christian H Lützhøft, Miguel V. Poulsen, Lisbeth Eriksen, Povl Krogsgaard-larsen

    Abstract:

    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.

  • Towards rational design of AMPA Receptor ligands: An integrated medicinal, computational, biostructural and molecular pharmacological approach
    Pharmacochemistry Library, 2020
    Co-Authors: A. Hogner, Stine B Vogensen, Jeremy R Greenwood, Jan Egebjerg, Tine B. Stensbøl, Jette S. Kastrup, Eva H. Møller, Povl Krogsgaard-larsen

    Abstract:

    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 ReceptorAgonist interactions.

Bjarke Ebert – 2nd expert on this subject based on the ideXlab platform

  • a tetrazolyl substituted subtype selective AMPA Receptor Agonist
    Journal of Medicinal Chemistry, 2007
    Co-Authors: Stine B Vogensen, Karla Frydenvang, Jeremy R Greenwood, Giovanna Postorino, Birgitte Nielsen, Darryl S Pickering, Bjarke Ebert, Ulrik Bolcho, Jan Egebjerg, Michael Gajhede

    Abstract:

    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.

  • Resolution, absolute stereochemistry and molecular pharmacology of the enantiomers of ATPA.
    European Journal of Pharmacology, 1999
    Co-Authors: Tine B. Stensbøl, Bjarke Ebert, Jan Egebjerg, Ulf Madsen, Tommy N. Johansen, Lars Borre, Povl Krogsgaard-larsen

    Abstract:

    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.

  • 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, 1998
    Co-Authors: Tommy N. Johansen, Bjarke Ebert, Ulf Madsen, Povl Krogsgaard-larsen, Hans Bräuner-osborne, Michael Didriksen, Karina Krøjer Søby, Inge T. Christensen, Lotte Brehm

    Abstract:

    (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.

Ulf Madsen – 3rd expert on this subject based on the ideXlab platform

  • Ionotropic excitatory amino acid Receptor ligands. Synthesis and pharmacology of a new amino acid AMPA antAgonist.
    European Journal of Medicinal Chemistry, 2020
    Co-Authors: Ulf Madsen, Tine B. Stensbøl, Frank A. Sløk, Hans Bräuner-osborne, Hans-christian H Lützhøft, Miguel V. Poulsen, Lisbeth Eriksen, Povl Krogsgaard-larsen

    Abstract:

    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.

  • Tetrazolyl isoxazole amino acids as ionotropic glutamate Receptor antAgonists: Synthesis, modelling and molecular pharmacology
    Bioorganic & Medicinal Chemistry, 2005
    Co-Authors: Bente Frølund, Jeremy R Greenwood, Birgitte Nielsen, Jan Egebjerg, Ulf Madsen, Tine B. Stensbøl, Hans Bräuner-osborne, Mai Marie Holm, Povl Krogsgaard-larsen

    Abstract:

    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.

  • Synthesis and in vitro pharmacology at AMPA and kainate preferring glutamate Receptors of 4-heteroarylmethylidene glutamate analogues
    Bioorganic & Medicinal Chemistry, 2003
    Co-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 Madsen

    Abstract:

    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.