Molecular pharmacology of 4-substituted glutamic acid analogues at ionotropic and metabotropic excitatory amino acid receptors

doi:10.1016/S0014-2999(97)01263-6

European Journal of Pharmacology

Volume 335, Issues 2–3, 24 September 1997, Pages R1-R3

https://doi.org/10.1016/S0014-2999(97)01263-6 Get rights and content

Abstract

The pharmacology of (2S,4R)-4-methylglutamic acid, (2S,4S)-4-methylglutamic acid and (S)- and (R)-4-methyleneglutamic acids (obtained in high chemical and enantiomeric purity from racemic 4-methyleneglutamic acid by chiral HPLC using a Crownpak CR(+) column), was examined in binding experiments using rat brain ionotropic glutamate receptors, and in functional assays using cloned metabotropic glutamate (mGlu) receptors. As a notable result of these studies, (2S,4R)-4-methylglutamic acid and (2S,4S)-4-methylglutamic acid were both shown to be selective for kainic acid receptors and mGlu receptors (subtypes 1α and 2), respectively, whereas (S)-4-methyleneglutamic acid showed high but rather non-selective affinity for the (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), kainic acid, NMDA and mGlu receptors (subtypes 1α and 2). Although none of the compounds were specific for any of the receptor subtypes, the results demonstrate that each of these structurally related compounds has a distinct pharmacological profile.

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Acknowledgements

The authors wish to thank Professor Shigetada Nakanishi (Kyoto University, Japan) for his generous gift of mGlu expressing cell lines and Ms. Heidi Petersen for technical assistance. This work was supported by H. Lundbeck A/S, The Lundbeck Foundation and The Danish State Biotechnology Program.

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Citation Excerpt :
We cannot rule out the possibility that at doses used in the present study, SYM 2081 may have bound to and been an agonist at AMPA, NMDA, or metabotrophic glutamate receptors. SYM 2081 has been shown to induce inward currents at AMPA (GluR1 and GluR3) and metabotrophic glutamate receptor subunits (mGluR1a, mGluR2, mGluR4a) expressed heterogeneously but at 1500-fold higher concentrations than required to evoke currents at the kainate receptor subunit (GluR5) that were similarly expressed [7,20,68]. Whether SYM 2081 evokes currents through NMDA receptors is unknown.
Excitatory amino acids acting at non-NMDA receptors contribute to transmission of nociceptive information. SYM 2081 ((2S,4R)-4-methyl glutamic acid) desensitizes kainate receptors, one subtype of non-NMDA receptors, to subsequent release of excitatory amino acids and thus may attenuate transmission of nociceptive information. To determine if SYM 2081 can prevent development of hyperalgesia, SYM 2081 (10, 50 or 100 mg/kg, i.p.) was administered prior to injection of capsaicin into the hindpaw of rats, which produces mechanical and heat hyperalgesia. To determine if SYM 2081 can reduce ongoing inflammatory hyperalgesia, SYM 2081 (10 or 100 mg/kg, i.p.) was administered after development of carrageenan-evoked hyperalgesia. Intraplantar injection of capsaicin produced an increase in hindpaw withdrawal frequency to mechanical stimuli (from 4±2 to 41±7%; mean±S.E.M.) and a decrease in withdrawal latency to heat (from 12.3±0.3 to 5.9±0.4 s) in rats that received vehicle. In contrast, rats that received SYM 2081 (100 mg/kg) prior to injection of capsaicin exhibited a lower hindpaw withdrawal frequency (18±4%) and a longer withdrawal latency (7.7±0.5 s). Intrathecal (1–100 μg/5 μl), but not intraplantar (10 or 100 μg/50 μl), injection of SYM 2081 attenuated the development of capsaicin-evoked heat hyperalgesia suggesting that SYM 2081’s antihyperalgesic effects were due to its central effects. Furthermore, SYM 2081 completely reversed ongoing carrageenan-evoked mechanical hyperalgesia and partially (∼50%) reversed ongoing heat hyperalgesia. The present study demonstrates that administration of a high-potency ligand that selectively desensitizes kainate receptors attenuates the development of mechanical and heat hyperalgesia and attenuates ongoing inflammatory hyperalgesia.
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Two hybrid analogues of the kainic acid receptor agonists, 2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA) and (2S,4R)-4-methylglutamic acid ((2S,4R)-4-Me-Glu), were designed, synthesized, and characterized in radioligand binding assays using cloned ionotropic and metabotropic glutamic acid receptors. The (S)-enantiomers of E-4-(2,2-dimethylpropylidene)glutamic acid ((S)-1) and E-4-(3,3-dimethylbutylidene)glutamic acid ((S)-2) were shown to be selective and high affinity GluR5 ligands, with K_i values of 0.024 and 0.39 μM, respectively, compared to K_i values at GluR2 of 3.0 and 2.0 μM, respectively. Their affinities in the [³H]AMPA binding assay on native cortical receptors were shown to correlate with their GluR2 affinity rather than their GluR5 affinity. No affinity for GluR6 was detected (IC₅₀>100 μM).
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Molecular pharmacology of 4-substituted glutamic acid analogues at ionotropic and metabotropic excitatory amino acid receptors

Abstract

Section snippets

Acknowledgements

Eur. J. Med. Chem.

Bioorg. Med. Chem.

A new highly selective metabotropic excitatory amino acid agonist: 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid

J. Med. Chem.

Efficient synthesis of 4-methylene-l-glutamic acid and its cyclopropyl analogue

Tetrahedron Asymmetry