The Glutamate Receptor GluR5 Agonist ( S )-2-Amino-3-(3-hydroxy-7,8-dihydro-6 H -cyclohepta[ d ]isoxazol-4-yl)propionic Acid and the 8-Methyl Analogue: Synthesis, Molecular Pharmacology, and Biostructural Characterization†PDB ID: 2WKY.
2009; American Chemical Society; Volume: 52; Issue: 15 Linguagem: Inglês
10.1021/jm900565c
ISSN1520-4804
AutoresRasmus P. Clausen, Peter Naur, Anders S. Kristensen, Jeremy R. Greenwood, Mette Strange, Hans Bräuner‐Osborne, Anders A. Jensen, Anne Sophie T. Nielsen, Ulla Geneser, Lone M. Ringgaard, Birgitte Nielsen, Darryl S. Pickering, Lotte Brehm, Michael Gajhede, Povl Krogsgaard‐Larsen, J.S. Kastrup,
Tópico(s)Bioactive Compounds and Antitumor Agents
ResumoThe design, synthesis, and pharmacological characterization of a highly potent and selective glutamate GluR5 agonist is reported. (S)-2-Amino-3-((RS)-3-hydroxy-8-methyl-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid (5) is the 8-methyl analogue of (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid ((S)-4-AHCP, 4). Compound 5 displays an improved selectivity profile compared to 4. A versatile stereoselective synthetic route for this class of compounds is presented along with the characterization of the binding affinity of 5 to ionotropic glutamate receptors (iGluRs). Functional characterization of 5 at cloned iGluRs using a calcium imaging assay and voltage-clamp recordings show a different activation of GluR5 compared to (S)-glutamic acid (Glu), kainic acid (KA, 1), and (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl)propionic acid ((S)-ATPA, 3) as previously demonstrated for 4. An X-ray crystallographic analysis of 4 and computational analyses of 4 and 5 bound to the GluR5 agonist binding domain (ABD) are presented, including a watermap analysis, which suggests that water molecules in the agonist binding site are important selectivity determinants.
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