title: A tetrazolyl-substituted subtype-selective AMPA receptor agonist.
abstract: Replacement of the methyl group of the AMPA receptor agonist 2-amino-3-[3-hydroxy-5-(2-methyl-2H-5-tetrazolyl)-4-isoxazolyl]propionic acid (2-Me-Tet-AMPA) with a benzyl group provided the first AMPA receptor agonist, compound 7, capable of discriminating GluR2-4 from GluR1 by its more than 10-fold preference for the former receptor subtypes. An X-ray crystallographic analysis of this new analogue in complex with the GluR2-S1S2J construct shows that accommodation of the benzyl group creates a previously unobserved pocket in the receptor, which may explain the remarkable pharmacological profile of compound 7.
authors: Department of Medicinal Chemistry, The Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
authors: Stine B
authors: SB
authors: Vogensen
authors: Karla
authors: K
authors: Frydenvang
authors: Jeremy R
authors: JR
authors: Greenwood
authors: Giovanna
authors: G
authors: Postorino
authors: Birgitte
authors: B
authors: Nielsen
authors: Darryl S
authors: DS
authors: Pickering
authors: Bjarke
authors: B
authors: Ebert
authors: Ulrik
authors: U
authors: Bølcho
authors: Jan
authors: J
authors: Egebjerg
authors: Michael
authors: M
authors: Gajhede
authors: Jette S
authors: JS
authors: Kastrup
authors: Tommy N
authors: TN
authors: Johansen
authors: Rasmus P
authors: RP
authors: Clausen
authors: Povl
authors: P
authors: Krogsgaard-Larsen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D066298:In Vitro Techniques; D007313:Insecta; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018408:Patch-Clamp Techniques; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists* / Q000737:chemistry / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014982:Xenopus laevis; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C520859:2-amino-3-(3-hydroxy-5-(2-benzyl-2H-5-tetrazolyl)-4-isoxazolyl)propionic acid; D018091:Receptors, AMPA; D013777:Tetrazoles; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C104722:glutamate receptor ionotropic, AMPA 2