title: 3-Acyl-4-hydroxyquinolin-2(1H)-ones. Systemically active anticonvulsants acting by antagonism at the glycine site of the N-methyl-D-aspartate receptor complex.
abstract: Most full antagonists at the glycine site of the NMDA receptor contain a carboxylic acid, which we believe to be detrimental to penetration of the blood-brain barrier. By consideration of a pharmacophore, novel antagonists at this site have been designed in which the anionic functionality is a vinylogous acid, in the form of a 4-hydroxyquinolin-2(1H)-one. In this series, a 3-substituent is necessary for binding, and correct manipulation of this group leads to compounds such as the 3-(3-hydroxyphenyl)propargyl ester 24 (L-701,273), with an IC50 for displacement of [3H]-L-689,560 binding of 0.17 microM and Kb against NMDA in the cortical slice of 1.39 microM. Compounds were tested for their ability to prevent audiogenic seizure in DBA/2 mice; the most potent compound in this series is the cyclopropyl ketone 42 (L-701,252), with an ED50 of 4.1 mg/kg ip. A model is proposed for binding to the glycine site, in which an important interaction is of a putative receptor cation with the pi-system of the 3-substituent.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Rowley
authors.forename: P D
authors.initials: PD
authors.lastname: Leeson
authors.forename: G I
authors.initials: GI
authors.lastname: Stevenson
authors.forename: A M
authors.initials: AM
authors.lastname: Moseley
authors.forename: I
authors.initials: I
authors.lastname: Stansfield
authors.forename: I
authors.initials: I
authors.lastname: Sanderson
authors.forename: L
authors.initials: L
authors.lastname: Robinson
authors.forename: R
authors.initials: R
authors.lastname: Baker
authors.forename: J A
authors.initials: JA
authors.lastname: Kemp
authors.forename: G R
authors.initials: GR
authors.lastname: Marshall
mesh_terms: D000215:Acylation; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002540:Cerebral Cortex / Q000378:metabolism / Q000648:ultrastructure; D005998:Glycine / Q000378:metabolism*; D006912:Hydroxyquinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D007659:Ketones / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D007769:Lactams / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D006912:Hydroxyquinolines; D007659:Ketones; D007769:Lactams; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine