Design, synthesis, and pharmacology of a highly subtype-selective GluR1/2 agonist, (RS)-2-amino-3-(4-chloro-3-hydroxy-5-isoxazolyl)propionic acid (Cl-HIBO)

J Med Chem. 2003 May 22;46(11):2246-9. doi: 10.1021/jm020588f.

Abstract

On the basis of structural studies, chloro-homoibotenic acid (Cl-HIBO) was designed and synthesized. Cl-HIBO was characterized in binding and electrophysiology experiments on native and cloned subtypes of GluRs. Electrophysiological selectivities ranged from 275 to 1600 for GluR1/2 over GluR3/4. The potent AMPA receptor activity was strongly desensitizing and the neurotoxicity similar to AMPA. Thus, Cl-HIBO is the most subtype selective agonist reported to date on GluR1/2, and offers a new standard for selectively studying subtypes of AMPA receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / physiology
  • Electrophysiology
  • Excitatory Amino Acid Agonists / chemical synthesis*
  • Excitatory Amino Acid Agonists / chemistry
  • Excitatory Amino Acid Agonists / pharmacology
  • In Vitro Techniques
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology
  • Mice
  • Models, Molecular
  • Neurons / drug effects
  • Oocytes / drug effects
  • Oocytes / physiology
  • Propionates / chemical synthesis*
  • Propionates / chemistry
  • Propionates / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, AMPA / agonists*
  • Receptors, Metabotropic Glutamate / drug effects
  • Stereoisomerism
  • Structure-Activity Relationship
  • Xenopus laevis

Substances

  • 2-amino-3-(4-chloro-3-hydroxy-5-isoxazolyl)propionic acid
  • Excitatory Amino Acid Agonists
  • Isoxazoles
  • Propionates
  • Receptors, AMPA
  • Receptors, Metabotropic Glutamate
  • glutamate receptor ionotropic, AMPA 2
  • glutamate receptor ionotropic, AMPA 1