title: Synthesis and SAR of 5-, 6-, 7- and 8-aza analogues of 3-aryl-4-hydroxyquinolin-2(1H)-one as NMDA/glycine site antagonists.
abstract: A series of 5-, 6-, 7- and 8-aza analogues of 3-aryl-4-hydroxyquinolin-2(1H)-one was synthesized and assayed as NMDA/glycine receptor antagonists. The in vitro potency of these antagonists was determined by displacement of the glycine site radioligand [(3)H]5,7-dicholorokynurenic acid ([(3)H]DCKA) in rat brain cortical membranes. Selected compounds were also tested for functional antagonism using electrophysiological assays in Xenopus oocytes expressing cloned NMDA receptor (NR) 1A/2C subunits. Among the 5-, 6-, 7-, and 8-aza-3-aryl-4-hydroxyquinoline-2(1H)-ones investigated, 5-aza-7-chloro-4-hydroxy-3-(3-phenoxyphenyl)quinolin-2-(1H)-one (13i) is the most potent antagonist, having an IC(50) value of 110 nM in [(3)H]DCKA binding and a K(b) of 11 nM in the electrophysiology assay. Compound 13i is also an active anticonvulsant when administered systemically in the mouse maximum electroshock-induced seizure test (ED(50)=2.3mg/kg, IP).
authors.affiliation: CoCensys, Inc., 213 Technology Drive, 92618, Irvine, CA, USA
authors.forename: Z L
authors.initials: ZL
authors.lastname: Zhou
authors.forename: J M
authors.initials: JM
authors.lastname: Navratil
authors.forename: S X
authors.initials: SX
authors.lastname: Cai
authors.forename: E R
authors.initials: ER
authors.lastname: Whittemore
authors.forename: S A
authors.initials: SA
authors.lastname: Espitia
authors.forename: J E
authors.initials: JE
authors.lastname: Hawkinson
authors.forename: M
authors.initials: M
authors.lastname: Tran
authors.forename: R M
authors.initials: RM
authors.lastname: Woodward
authors.forename: E
authors.initials: E
authors.lastname: Weber
authors.forename: J F
authors.initials: JF
authors.lastname: Keana
mesh_terms: D000818:Animals; D005998:Glycine / Q000737:chemistry / Q000378:metabolism; D009865:Oocytes; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014316:Tritium; D014981:Xenopus
chemical_list: D015363:Quinolones; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D005998:Glycine