Synthesis and in vitro pharmacology at AMPA and kainate preferring glutamate receptors of 4-heteroarylmethylidene glutamate analogues

• Published in: Bioorganic & medicinal chemistry 2003-10, Vol.11 (20), p.4341-4349
• Main Authors: Valgeirsson, Jon, Christensen, Jeppe K., Kristensen, Anders S., Pickering, Darryl S., Nielsen, Birgitte, Fischer, Christina H., Bräuner-Osborne, Hans, Nielsen, Elsebet Ø., Krogsgaard-Larsen, Povl, Madsen, Ulf
• Format: Article
• Language: English
• Subjects: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - chemistry; Animals; Biological and medical sciences; Cell Line; Cerebellar Cortex - chemistry; Cerebellar Cortex - metabolism; Electrophysiology; Excitatory Amino Acid Agonists - chemistry; Glutamatergic system (aspartate and other excitatory aminoacids); Glutamic Acid - analogs & derivatives; Humans; Kainic Acid - chemistry; Ligands; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Radioligand Assay; Rats; Receptors, AMPA - chemistry; Receptors, Glutamate - chemistry; Receptors, Kainic Acid - chemistry; Substrate Specificity
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(03)00485-1

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. Compound 4a was shown to be a potent GluR5 agonist with lower affinities towards the AMPA receptor subtypes GluR1–4.