title: 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.
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.
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK 2100 Copenhagen, Denmark.|Department of Biochemistry and Molecular Biology, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing Normal University , Beijing 100875, P. R. of China.
authors: Shuang-Yan
authors: SY
authors: Wang
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK 2100 Copenhagen, Denmark.
authors: Younes
authors: Y
authors: Larsen
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK 2100 Copenhagen, Denmark.
authors: Cristina Vara
authors: CV
authors: Navarrete
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK 2100 Copenhagen, Denmark.
authors: Anders A
authors: AA
authors: Jensen
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK 2100 Copenhagen, Denmark.
authors: Birgitte
authors: B
authors: Nielsen
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK 2100 Copenhagen, Denmark.
authors: Ali
authors: A
authors: Al-Musaed
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK 2100 Copenhagen, Denmark.
authors: Karla
authors: K
authors: Frydenvang
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK 2100 Copenhagen, Denmark.
authors: Jette Sandholm
authors: JS
authors: Kastrup
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK 2100 Copenhagen, Denmark.
authors: Darryl S
authors: DS
authors: Pickering
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK 2100 Copenhagen, Denmark.
authors: Rasmus Prætorius
authors: RP
authors: Clausen
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007555:Isoxazoles; D018091:Receptors, AMPA; D000409:Alanine