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.
Esben J Bjerrum  1 ,  Anders S Kristensen ,  Darryl S Pickering ,  Jeremy R Greenwood ,  Birgitte Nielsen ,  Tommy Liljefors ,  Arne Schousboe ,  Hans Bräuner-Osborne ,  Ulf Madsen
Affiliations
  • 1. Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
PMID: 12747796 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.

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