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).
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.
Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
Esben J
EJ
Bjerrum
Anders S
AS
Kristensen
Darryl S
DS
Pickering
Jeremy R
JR
Greenwood
Birgitte
B
Nielsen
Tommy
T
Liljefors
Arne
A
Schousboe
Hans
H
Bräuner-Osborne
Ulf
U
Madsen
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists*; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D018690:Excitatory Amino Acid Agonists; D007555:Isoxazoles; D011422:Propionates; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; C474829:2-amino-3-(4-chloro-3-hydroxy-5-isoxazolyl)propionic acid; C104722:glutamate receptor ionotropic, AMPA 2