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)

Esben J Bjerrum; Anders S Kristensen; Darryl S Pickering; Jeremy R Greenwood; Birgitte Nielsen; Tommy Liljefors; Arne Schousboe; Hans Bräuner-Osborne; Ulf Madsen

doi:10.1021/jm020588f

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.

Authors

Esben J Bjerrum¹, Anders S Kristensen, Darryl S Pickering, Jeremy R Greenwood, Birgitte Nielsen, Tommy Liljefors, Arne Schousboe, Hans Bräuner-Osborne, Ulf Madsen

Affiliation

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.

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