title: 4-Alkyl- and 4-cinnamylglutamic acid analogues are potent GluR5 kainate receptor agonists.
abstract: Enantiomerically pure (2S,4R)-4-substituted glutamic acids were prepared and tested for homomeric GluR5 and GluR6 kainate subtype receptor affinity. Some of the 4-cinnamyl analogues showed high selectivity and potency (K(i) < 25 nM) for the GluR5 receptors. The greatest selectivity and potency were achieved with the 3-(2-naphthyl)prop-2-enyl compound. This compound, LY339434, has negligible activity at the AMPA and kainate receptors GluR1, -2, -4 and -6. Although, LY339434 shows agonist activity at NMDA receptors in cultural hippocampal neurons (approximate EC(50) of 2.5 microM), we consider that LY339434 should be a useful pharmacological tool for the investigation of the functional role of GluR5 kainate receptors.
authors.affiliation: Lilly, S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Pedregal
authors.forename: I
authors.initials: I
authors.lastname: Collado
authors.forename: A
authors.initials: A
authors.lastname: Escribano
authors.forename: J
authors.initials: J
authors.lastname: Ezquerra
authors.forename: C
authors.initials: C
authors.lastname: Domínguez
authors.forename: A I
authors.initials: AI
authors.lastname: Mateo
authors.forename: A
authors.initials: A
authors.lastname: Rubio
authors.forename: S R
authors.initials: SR
authors.lastname: Baker
authors.forename: J
authors.initials: J
authors.lastname: Goldsworthy
authors.forename: R K
authors.initials: RK
authors.lastname: Kamboj
authors.forename: B A
authors.initials: BA
authors.lastname: Ballyk
authors.forename: K
authors.initials: K
authors.lastname: Hoo
authors.forename: D
authors.initials: D
authors.lastname: Bleakman
mesh_terms: D000114:Acetylene / Q000737:chemistry; D002460:Cell Line; D002478:Cells, Cultured; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000502:physiology; D005971:Glutamates / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000819:agonists* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000114:Acetylene; D005971:Glutamates; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; C117450:2-amino-4-carboxy-7-(2-naphthyl)hept-6-enoic acid