AMPA Receptor Agonists:  Synthesis, Protolytic Properties, and Pharmacology of 3-Isothiazolol Bioisosteres of Glutamic Acid

Matzen, Lisa; Engesgaard, A.; Ebert, Bjarke; Didriksen, Michael; Frølund, Bente; Krogsgaard‐Larsen, Povl; Jaroszewski, Jerzy W.

doi:10.1021/jm9607212

Cited by 43 publications

(59 citation statements)

References 43 publications

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“…4D, w1) is found near Gly-653 (equivalent to Gly-675 in GluR-D) only in the AMPA complex. This water molecule plays a key role in agonist binding, forming hydrogen bonds with the oxygen atom at the 3-position of the isoxazole ring, shown to be unprotonated (21), to the ␣-carboxylate of AMPA, and to the main chain NH group of Thr-655 (Thr-677 in GluR-D). The distance between the ␣-carbon of Gly-653 to the oxygen atom of w1 is 3.3 Å, whereas with the glycine-to-alanine mutation, the distance between the methyl carbon in the alanine side chain and w1 would be only about 2.0 Å (Fig.…”

Section: Resultsmentioning

confidence: 99%

Discrimination between Agonists and Antagonists by the α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid-selective Glutamate Receptor

Lampinen¹,

Settimo²,

Pentikäinen³

et al. 2002

Journal of Biological Chemistry

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The ligand-binding site of ionotropic glutamate receptors is composed of two extracellular segments, S1 and S2, homologous to bacterial amino acid-binding proteins (1-3). Recent determination of the crystal structure of an S1S2 fusion protein of the GluR-B 1 (GluR2) ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit as complexed with ligands (4, 5) provided the first atomic resolution view into a neurotransmitter-binding pocket and confirmed the earlier predictions of a close structural and functional similarity to the bacterial proteins (1-3, 6 -9). The agonists kainate, glutamate, and AMPA are engaged in multiple polar and van der Waals contacts that stabilize a closed state of the two-lobed binding domain (4, 5). The charged ␣-aminocarboxylate group of glutamate and AMPA and the pyrrolidine carboxyl and imino groups of kainate are accommodated by hydrogen bonds and ion pair interactions with the oppositely charged side chains of Arg-485 and Glu-705, respectively. The distal negatively charged group of the agonists, the carboxylmethyl group of kainate, the ␥-carboxylate of glutamate, or the isoxazole ring hydroxyl of AMPA, make close polar contacts with the base of an ␣-helix ("helix F") in the lobe 2, but the exact hydrogen bonding patterns differ between agonists (4,5). In contrast to the agonist complexes, the ligand-free apo form and one antagonist complex (6,7-dinitroquinoxaline-2,3-dione (DNQX)) of GluR-B S1S2 assume a more open state, suggesting that agonist activity is based on their ability to induce a slight closure of the lobes (5).Although the stereochemical features of the agonist-receptor interaction revealed by the crystal structure are largely supported by mutagenesis data, not much is yet known on how the receptor discriminates between agonists and antagonists or on how structurally different antagonists interact with the receptor. In particular, it is currently unclear to what extent the contacts antagonists make with the receptor overlap those made by agonists. Although previous mutagenesis work has identified amino acid residues that affect antagonist affinities in the AMPA receptor, for example , no mutations that would selectively affect only agonists or antagonists have been reported. As a step toward understanding the structural basis of discrimination between agonists and antagonists by AMPA receptors, we have analyzed the ligand binding properties of the mutated GluR-D ligand-binding domain constructs by using [ 3 H]AMPA, an agonist, and [ 3 H]Ro 48-8587, a high affinity AMPA receptor an-* This study was financially supported by the Academy of Finland and the National Technology Agency of Finland (TEKES). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.ʈ To whom correspondence should be addressed: Dept. of Biosciences, Viikinkaari 5D, 00014 University of Helsinki, Helsinki, Finland....

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Section: Resultsmentioning

confidence: 99%

Discrimination between Agonists and Antagonists by the α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid-selective Glutamate Receptor

Lampinen¹,

Settimo²,

Pentikäinen³

et al. 2002

Journal of Biological Chemistry

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“…For stimulation of glutamate receptors (NMDA, AMPA, Kainate and metabotropic receptor) four agonists were used, respectively: trans-1-Aminocyclobutan-1,3-dicarboxylic acid (ACBD [13], (S)-(-)-α-Amino-5-fluoro-3,4-dihydro-2,4-dioxo-1(2H)-pyrimmidinepropanoic acid (S-Fluorowillardiine [14]- [16], (RS)-2-Amino-3-(3-hydroxy-5-tert-butyliosxazol-4-yl)propanoic acid (ATPA; [17]- [20] and (±)-1-Aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD; [21]- [23]. All agonists were tested in pilot experiments in order to detect a concentration leading to strong increases of population spike amplitude in the presence of single stimuli (SS) and theta burst stimulation (TBS).…”

Section: Hippocampal Slice Preparation In Vitromentioning

confidence: 99%

Mechanism of Action of Low Dose Preparations from Coffea arabica, Gelsemium and Veratrum Based on in Vivo and in Vitro Neurophysiological Findings

Dimpfel¹,

Biller²

2015

JBBS

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Low dose remedies are widely administered in medicine. We used Tele-Stereo-EEG and the hippocampal slice preparation to measure physiological effects of orally given Coffea D6 (40 mg/kg), Gelsemium D4 (10 mg/kg) and Veratrum D6 (30 mg/kg) in rats. Adult rats were implanted with electrodes positioned stereotactically into four brain regions. Changes in field potentials were transmitted wirelessly. After frequency analysis data from 6 -8 animals were averaged. For in vitro testing, preparations were superfused directly on hippocampal slices. Stimulation of Schaffer Collaterals by single stimuli (SS) or theta burst stimulation (TBS) resulted in stable population spike amplitudes. All three low dose preparations produced decreases of spectral power. Statistically significant changes were observed in delta, theta and alpha2 spectral power. In the hippocampal slice preparation Coffea facilitated signal transfer presumably by enhancing glutamate AMPA receptor transmission. Gelsemium showed a similar effect, but only after single shock stimulation. Opposite to this, attenuation of the electric pathway was recognized after theta burst stimulation due to AMPA receptor and glutamate metabotropic II receptor mediated transmission. Veratrum was able to attenuate glutamatergic due to receptor-mediated signalling sensitive to AMPA and NMDA. The results strongly speak in favour of the existence of biologically active molecules in these low dose preparations.

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“…5). Replacement of the 3-isoxazolol acidic moiety of AMPA with the corresponding 3-isothiazolol provided thio-AMPA 48 (Fig. 4).…”

Section: Ampa Analogsmentioning

confidence: 99%

“…Although the pKa value of the distal acidic group of AMPA is almost two units lower than that of thio-AMPA, comparable selectivity and activity at AMPA receptors were observed for AMPA and thio-AMPA. 48 Resolution of thio-AMPA and pharmacological characterization of the enantiomers revealed that the affinity and agonist activity resides exclusively in the S-enantiomer 49 ( Table 1). As in the case of (R)-AMPA, no antagonist effects were observed for (R)-thio-AMPA on the rat cortical wedge.…”

Section: Ampa Analogsmentioning

confidence: 99%

Stereostructure–activity studies on agonists at the AMPA and kainate subtypes of ionotropic glutamate receptors

Johansen¹,

Greenwood²,

Frydenvang³

et al. 2003

Chirality

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(S)-Glutamic acid (Glu), the major excitatory neurotransmitter in the central nervous system, operates through ionotropic as well as metabotropic receptors and is considered to be involved in certain neurological disorders and degenerative brain diseases that are currently without any satisfactory therapeutic treatment. Until recently, development of selective Glu receptor agonists had mainly been based on lead compounds, which were frequently naturally occurring excitants structurally related to Glu. These Glu receptor agonists generally contain heterocyclic acidic moieties, which has stimulated the use of bioisosteric replacement approaches for the design of subtype-selective agonists. Furthermore, most of these leads are conformationally restricted and stereochemically well-defined Glu analogs. Crystallization of the agonist binding domain of the GluR2 subunit of the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtype of ionotropic Glu receptors in the presence or absence of an agonist has provided important information about ligand-receptor interaction mechanisms. The availability of these binding domain crystal structures has formed the basis for rational design of ligands, especially for the AMPA and kainate subtypes of ionotropic Glu receptors. This mini-review will focus on structure-activity relationships on AMPA and kainate receptor agonists with special emphasis on stereochemical and three-dimensional aspects.

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AMPA Receptor Agonists: Synthesis, Protolytic Properties, and Pharmacology of 3-Isothiazolol Bioisosteres of Glutamic Acid

Cited by 43 publications

References 43 publications

Discrimination between Agonists and Antagonists by the α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid-selective Glutamate Receptor

Discrimination between Agonists and Antagonists by the α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid-selective Glutamate Receptor

Mechanism of Action of Low Dose Preparations from <i>Coffea arabica</i>, <i>Gelsemium</i> and <i>Veratrum</i> Based on <i>in Vivo</i> and <i>in Vitro</i> Neurophysiological Findings

Stereostructure–activity studies on agonists at the AMPA and kainate subtypes of ionotropic glutamate receptors

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AMPA Receptor Agonists: Synthesis, Protolytic Properties, and Pharmacology of 3-Isothiazolol Bioisosteres of Glutamic Acid

Cited by 43 publications

References 43 publications

Discrimination between Agonists and Antagonists by the α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid-selective Glutamate Receptor

Discrimination between Agonists and Antagonists by the α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid-selective Glutamate Receptor

Mechanism of Action of Low Dose Preparations from &lt;i&gt;Coffea arabica&lt;/i&gt;, &lt;i&gt;Gelsemium&lt;/i&gt; and &lt;i&gt;Veratrum&lt;/i&gt; Based on &lt;i&gt;in Vivo&lt;/i&gt; and &lt;i&gt;in Vitro&lt;/i&gt; Neurophysiological Findings

Stereostructure–activity studies on agonists at the AMPA and kainate subtypes of ionotropic glutamate receptors

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Product

Resources

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Mechanism of Action of Low Dose Preparations from <i>Coffea arabica</i>, <i>Gelsemium</i> and <i>Veratrum</i> Based on <i>in Vivo</i> and <i>in Vitro</i> Neurophysiological Findings