1. Tweaking Subtype Selectivity and Agonist Efficacy at (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) Receptors in a Small Series of BnTetAMPA Analogues.
- Author
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Wang SY, Larsen Y, Navarrete CV, Jensen AA, Nielsen B, Al-Musaed A, Frydenvang K, Kastrup JS, Pickering DS, and Clausen RP
- Subjects
- Alanine chemical synthesis, Alanine chemistry, Alanine pharmacology, Animals, Brain drug effects, Brain metabolism, Crystallography, X-Ray, Dose-Response Relationship, Drug, HEK293 Cells, Humans, Isoxazoles chemical synthesis, Isoxazoles chemistry, Models, Molecular, Molecular Structure, Rats, Receptors, AMPA metabolism, Structure-Activity Relationship, Alanine analogs & derivatives, Isoxazoles pharmacology, Receptors, AMPA agonists
- Abstract
A series of analogues of the (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptor agonist BnTetAMPA (5b) were synthesized and characterized pharmacologically in radioligand binding assays at native and cloned AMPA receptors and functionally by two-electrode voltage clamp electrophysiology at the four homomeric AMPA receptors expressed in Xenopus laevis oocytes. The analogues 6 and 7 exhibit very different pharmacological profiles with binding affinity preference for the subtypes GluA1 and GluA3, respectively. X-ray crystal structures of three ligands (6, 7, and 8) in complex with the agonist binding domain (ABD) of GluA2 show that they induce full domain closure despite their low agonist efficacies. Trp767 in GluA2 ABD could be an important determinant for partial agonism of this compound series at AMPA receptors, since agonist efficacy also correlated with the location of the Trp767 side chain.
- Published
- 2016
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