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
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Journal of Medicinal Chemistry |
Volume | 59 |
Issue number | 5 |
Pages (from-to) | 2244-2254 |
Number of pages | 11 |
ISSN | 0022-2623 |
DOIs | |
Publication status | Published - 2016 |
ID: 154014642