Abstract:
:2-Amino-3-[3-hydroxy-5-(2-thiazolyl)-4-isoxazolyl]propionic acid (1) is a potent AMPA receptor agonist with moderate affinity for native kainic acid (KA) receptors, whereas (S)-E-4-(2,2-dimethylpropylidene)glutamic acid (3) show high affinity for the GluR5 subtype of KA receptors and much lower affinity for the GluR2 subtype of AMPA receptors. As an attempt to develop new pharmacological tools for studies of GluR5 receptors, (S)-E-4-(2-thiazolylmethylene)glutamic acid (4a) was designed as a structural hybrid between 1 and 3. 4a was shown to be a potent GluR5 agonist and a high affinity ligand and to indiscriminately bind to the AMPA receptor subtypes GluR1-4 with lower affinities. Compounds 4b-h, in which the 2-thiazolyl substituent of 4a was replaced by other heterocyclic rings, which have previously been incorporated as 5-substituents in AMPA analogues, as exemplified by 1 were also synthesized. Compounds 4b-h were either inactive (4e,f) or weaker than 4a as affinity ligands for GluR1-4 and GluR5 with relative potencies comparable with those of the corresponding AMPA analogues as AMPA receptor agonists. Compounds 4a-h may be useful tools for the progressing pharmacophore mapping of the GluR5 agonist binding site.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Valgeirsson J,Christensen JK,Kristensen AS,Pickering DS,Nielsen B,Fischer CH,Bräuner-Osborne H,Nielsen EØ,Krogsgaard-Larsen P,Madsen Udoi
10.1016/s0968-0896(03)00485-1subject
Has Abstractpub_date
2003-10-01 00:00:00pages
4341-9issue
20eissn
0968-0896issn
1464-3391pii
S0968089603004851journal_volume
11pub_type
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