The Glutamate Receptor GluR5 Agonist (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic Acid and the 8-methyl Analogue: Synthesis, Molecular Pharmacology, and Biostructural Characterization

J Med Chem. 2009 Aug 13;52(15):4911-22. doi: 10.1021/jm900565c.

Abstract

The 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Crystallography, X-Ray
  • Drug Design
  • Excitatory Amino Acid Agonists / chemical synthesis*
  • Excitatory Amino Acid Agonists / chemistry
  • Excitatory Amino Acid Agonists / pharmacology
  • Humans
  • Models, Molecular
  • Propionates / chemical synthesis
  • Propionates / chemistry
  • Propionates / pharmacology
  • Receptors, Kainic Acid / agonists*
  • Receptors, Kainic Acid / chemistry
  • Receptors, Kainic Acid / physiology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Xenopus laevis

Substances

  • Excitatory Amino Acid Agonists
  • Gluk1 kainate receptor
  • Propionates
  • Receptors, Kainic Acid

Associated data

  • PDB/2WKY