Abstract
It is generally agreed that (S)-glutamic acid (Glu) receptors are involved in the development of a number of diseases in the central nervous system (CNS), and ligands that interact with these receptors are of significant interest. Selective ligands are indispensable as tools for the elucidation of the physiological role of AMPA receptors and as leads for the development of therapeutic agents. Over the last decade a wide variety of such ligands have been developed and studies on the structure-activity relationships of these compounds have contributed to our understanding of the mechanisms involved in AMPA receptor activation and blockade. Series of selective agonists using the 3-isoxazolol amino acid ibotenic acid (2) as a lead compound have been designed and developed. Other heterocycles, such as the uracil moiety of willardiine (6), have also proved to be highly effective bioisosteres for the distal carboxyl group of Glu. For a number of reasons, the development of competitive antagonists with therapeutic potential has been hampered for example due to the limited solubility of key heterocyclic compounds structurally unrelated to Glu. However, some problems have been overcome, and series of water-soluble, potent and selective quinoxalinediones, indenoimidazones and isatine oximes have now been developed. At the turn of the millennium the crystal structure of GluR2 co-crystallized with different AMPA receptor ligands became available, opening a new era in the design of AMPA receptor ligands on a rational basis.
Keywords: ampa receptor, agonists, antagonists, (s)-glutamic acid, excitatory amino acids, ampa receptor agonists, ampa analogues, ibotenic acid analogues, bicyclic ampa analogues, ampa receptor antagonists
Current Pharmaceutical Design
Title: The AMPA Receptor Binding Site: Focus on Agonists and Competitive Antagonists
Volume: 8 Issue: 10
Author(s): Tine Bryan Stensbol, Ulf Madsen and Povl Krogsgaard-Larsen
Affiliation:
Keywords: ampa receptor, agonists, antagonists, (s)-glutamic acid, excitatory amino acids, ampa receptor agonists, ampa analogues, ibotenic acid analogues, bicyclic ampa analogues, ampa receptor antagonists
Abstract: It is generally agreed that (S)-glutamic acid (Glu) receptors are involved in the development of a number of diseases in the central nervous system (CNS), and ligands that interact with these receptors are of significant interest. Selective ligands are indispensable as tools for the elucidation of the physiological role of AMPA receptors and as leads for the development of therapeutic agents. Over the last decade a wide variety of such ligands have been developed and studies on the structure-activity relationships of these compounds have contributed to our understanding of the mechanisms involved in AMPA receptor activation and blockade. Series of selective agonists using the 3-isoxazolol amino acid ibotenic acid (2) as a lead compound have been designed and developed. Other heterocycles, such as the uracil moiety of willardiine (6), have also proved to be highly effective bioisosteres for the distal carboxyl group of Glu. For a number of reasons, the development of competitive antagonists with therapeutic potential has been hampered for example due to the limited solubility of key heterocyclic compounds structurally unrelated to Glu. However, some problems have been overcome, and series of water-soluble, potent and selective quinoxalinediones, indenoimidazones and isatine oximes have now been developed. At the turn of the millennium the crystal structure of GluR2 co-crystallized with different AMPA receptor ligands became available, opening a new era in the design of AMPA receptor ligands on a rational basis.
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Cite this article as:
Stensbol Bryan Tine, Madsen Ulf and Krogsgaard-Larsen Povl, The AMPA Receptor Binding Site: Focus on Agonists and Competitive Antagonists, Current Pharmaceutical Design 2002; 8 (10) . https://dx.doi.org/10.2174/1381612024607090
DOI https://dx.doi.org/10.2174/1381612024607090 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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