title: [EFfect of quinazolone-alkyl-carboxylic acid derivatives on the transmembrane Ca2+ ion flux mediated by AMPA receptors].
abstract: The excitatory neurotransmitter, Glu, plays a crucial role in many sensory and motor functions as well as in brain development, learning and memory and it is also involved in the pathogenesis of a number of neurological disorders, including epilepsy, Alzheimer's and Parkinson's diseases. Therefore, the study of Glu receptors (GluRs) is of therapeutical importance. We showed here by fluorescence monitoring of transmembrane Ca2+ ion fluxes in response to (S)-alpha-amino-3-hidroxi-5-metil-4-izoxazol propionic acid ((S)-AMPA) on the time scale of 0.00004-10 s that Ca2+ ion influx proceeds through faster and slower desensitizing receptors. Pharmacological isolation of the slower and faster desensitizing AMPA receptor was possible by fluorescence monitoring of Ca2+ ion translocation in response to (S)-AMPA in the presence and absence of various 2-methyl-4-oxo-3H-quinazoline-3-alkyl-carboxilic acid derivatives (Qxs): the acetic acid Q1 inhibits the slower desensitizing receptor response specifically, while the acetyl-piperidine Q5 is a more potent inhibitor of the faster desensitizing receptor response. In addition, spontaneous interictal activity, as induced by high [K+] conditions in hippocampal slices, was reduced significantly by Q5, suggesting a possible anticonvulsant property of Q5. Substitutions of Qxs into the GluR2 S1S2 binding core were consistent with their effect by causing variable degree of S1S2 bridging interaction as one of the main determinants of AMPA receptor agonist activity. The exploitation of differences between similar receptors will be important in the development and use of drugs with high pharmacological specificity.
authors.affiliation: Magyar Tudományos Akadémia, Kémiai Kutatóközpont, Kémiai Intézet, Neurokémiai Osztály, Budapest, Pusztaszeri út 59-67.-1025.
authors.forename: Eva
authors.initials: E
authors.lastname: Szárics
authors.forename: Bálint
authors.initials: B
authors.lastname: LaszTóczi
authors.forename: Lajos
authors.initials: L
authors.lastname: Nyikos
authors.forename: Péter
authors.initials: P
authors.lastname: Barabás
authors.forename: Ilona
authors.initials: I
authors.lastname: Kovács
authors.forename: Nina
authors.initials: N
authors.lastname: Skuban
authors.forename: Péter I
authors.initials: PI
authors.lastname: Nagy
authors.forename: József
authors.initials: J
authors.lastname: Kökösi
authors.forename: Novák Krisztina
authors.initials: NK
authors.lastname: Takácsné
authors.forename: Julianna
authors.initials: J
authors.lastname: Kardos
mesh_terms: D000478:Alkylation; D001927:Brain Diseases / Q000503:physiopathology; D002118:Calcium / Q000502:physiology*; D002264:Carboxylic Acids; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D006801:Humans; D011799:Quinazolines / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000187:drug effects / Q000502:physiology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D002264:Carboxylic Acids; D011799:Quinazolines; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002118:Calcium