Linked Life Data

12672235

Source:http://linkedlifedata.com/resource/pubmed/id/12672235

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
2003-4-3
pubmed:abstractText
We have previously described (RS)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid (4-AHCP) as a highly effective agonist at non-N-methyl-d-aspartate (non-NMDA) glutamate (Glu) receptors in vivo, which is more potent than (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) but inactive at NMDA receptors. However, 4-AHCP was found to be much weaker than AMPA as an inhibitor of [(3)H]AMPA binding and to have limited effect in a [(3)H]kainic acid binding assay using rat cortical membranes. To shed light on the mechanism(s) underlying this quite enigmatic pharmacological profile of 4-AHCP, we have now developed a synthesis of (S)-4-AHCP (6) and (R)-4-AHCP (7). At cloned metabotropic Glu receptors mGluR1alpha (group I), mGluR2 (group II), and mGluR4a (group III), neither 6 nor 7 showed significant agonist or antagonist effects. The stereoisomer 6, but not 7, activated cloned AMPA receptor subunits GluR1o, GluR3o, and GluR4o with EC(50) values in the range 4.5-15 microM and the coexpressed kainate-preferring subunits GluR6 + KA2 (EC(50) = 6.4 microM). Compound 6, but not 7, proved to be a very potent agonist (EC(50) = 0.13 microM) at the kainate-preferring GluR5 subunit, equipotent with (S)-2-amino-3-(5-tert-butyl-3-hydroxyisothiazol-4-yl)propionic acid [(S)-Thio-ATPA, 4] and almost 4 times more potent than (S)-2-amino-3-(5-tert-butyl-3-hydroxyisoxazol-4-yl)propionic acid [(S)-ATPA, 3]. Compound 6 thus represents a new structural class of GluR5 agonists. Molecular modeling and docking to a crystal structure of the extracellular binding domain of the AMPA subunit GluR2 has enabled identification of the probable active conformation and binding mode of 6. We are able to rationalize the observed selectivities by comparing the docking of 4 and 6 to subtype constructs, i.e., a crystal structure of the extracellular binding domain of GluR2 and a homology model of GluR5.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
10
pubmed:volume
46
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1350-8
pubmed:dateRevised
2010-1-13
pubmed:meshHeading
pubmed-meshheading:12672235-Alanine, pubmed-meshheading:12672235-Amino Acid Sequence, pubmed-meshheading:12672235-Animals, pubmed-meshheading:12672235-CHO Cells, pubmed-meshheading:12672235-Cricetinae, pubmed-meshheading:12672235-Excitatory Amino Acid Agonists, pubmed-meshheading:12672235-Isoxazoles, pubmed-meshheading:12672235-Ligands, pubmed-meshheading:12672235-Models, Molecular, pubmed-meshheading:12672235-Molecular Conformation, pubmed-meshheading:12672235-Molecular Sequence Data, pubmed-meshheading:12672235-Monte Carlo Method, pubmed-meshheading:12672235-Oocytes, pubmed-meshheading:12672235-Patch-Clamp Techniques, pubmed-meshheading:12672235-Propionic Acids, pubmed-meshheading:12672235-Radioligand Assay, pubmed-meshheading:12672235-Receptors, Kainic Acid, pubmed-meshheading:12672235-Sequence Homology, Amino Acid, pubmed-meshheading:12672235-Stereoisomerism, pubmed-meshheading:12672235-Structure-Activity Relationship, pubmed-meshheading:12672235-Xenopus laevis
pubmed:year
2003
pubmed:articleTitle
(S)-2-Amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid, a potent and selective agonist at the GluR5 subtype of ionotropic glutamate receptors. Synthesis, modeling, and molecular pharmacology.
pubmed:affiliation
Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't