PMID: 7523673Sep 30, 1994Paper

Synthesis and structure-activity studies on acidic amino acids and related diacids as NMDA receptor ligands

Journal of Medicinal Chemistry
T N JohansenU Madsen

Abstract

The 3-isoxazolol amino acids (S)-2-amino-3-(3-hydroxy-5-methyl-4- isoxazolyl)propionic acid [(S)-AMPA, 2] and (R,S)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid (AMAA, 5a) (Figure 1) are potent and specific agonists at the AMPA and N-methyl-D-aspartic acid (NMDA) subtypes, respectively, of (S)-glutamic acid (1) receptors. A number of amino acids and diacids structurally related to AMAA were synthesized and tested electrophysiologically and in receptor-binding assays. The hydroxymethyl analogue 7c of AMAA was an NMDA agonist approximately equipotent with AMAA in the [3H]CPP-binding assay (IC50 = 7 +/- 3 microM) and electropharmacologically in the rat cortical wedge model (EC50 = 8 +/- 2 microM). In contrast to this, the tertbutyl analogue 7a of AMAA turned out to be an antagonist at NMDA and AMPA receptors. The conformational characteristics of AMAA and 7a, c were studied by molecular mechanics calculations. Compound 7a possesses extra steric bulk and shows significant restriction of conformational flexibility compared to AMAA and 7c, which may be determining factors for the observed differences in biological activity. Although the nitrogen atom of quinolinic acid (6) has very weak basic character, 6 is a, perhaps subt...Continue Reading

Citations

Mar 1, 2012·European Journal of Pharmacology·Suzanne L HansenHenrik T Vestergaard
Sep 1, 1996·Journal of Receptor and Signal Transduction Research·G Höfner, K T Wanner
May 20, 1998·Natural Product Reports·M G Moloney
Aug 29, 1997·Journal of Medicinal Chemistry·B Bang-AndersenP Krogsgaard-Larsen

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