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

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Shuang-Yan Wang, Younes Larsen, Cristina V. Navarrete, Anders A. Jensen, Birgitte Nielsen, Ali Al-Musaed, Karla Frydenvang, Jette Sandholm Kastrup, Darryl S Pickering, Rasmus Prætorius Clausen

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 languageEnglish
JournalJournal of Medicinal Chemistry
Volume59
Issue number5
Pages (from-to)2244-2254
Number of pages11
ISSN0022-2623
DOIs
Publication statusPublished - 2016

ID: 154014642