title: 2-arylureidobenzoic acids: selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5.
abstract: A series of 2-arylureidobenzoic acids (AUBAs) was prepared by a short and effective synthesis, and the pharmacological activity at glutamate receptors was evaluated in vitro and in vivo. The compounds showed noncompetitive antagonistic activity at the kainate receptor subtype GluR5. The most potent compounds showed more than 50-fold selectivity for GluR5 compared to GluR6 and the AMPA receptor subtypes GluR1-4. The structure-activity relationships for the AUBAs showed distinct structural requirements for the substituents on the two aromatic ring systems. Only para-substituents were tolerated on the benzoic acid moiety (ring A), whereas ring B tolerated a variety of substituents, but with a preference for lipophilic substituents. The most potent compounds had a 4-chloro substituent on ring A and 3-chlorobenzene (6b), 2-naphthalene (8h), or 2-indole (8k) as ring B and had IC(50) values of 1.3, 1.2, and 1.2 microM, respectively, in a functional GluR5 assay. Compound 6c (IC(50) = 4.8 microM at GluR5) showed activity in the in vivo ATPA rigidity test, indicating that 6c has better pharmacokinetic properties than 8h, which was inactive in this test. The AUBAs are the first example of a series of noncompetitive GluR5-selective antagonists and may prove to be important pharmacological tools and leads in the search for therapeutic glutamatergic agents.
authors.affiliation: Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
authors.forename: Jon
authors.initials: J
authors.lastname: Valgeirsson
authors.forename: Elsebet Ø
authors.initials: EØ
authors.lastname: Nielsen
authors.forename: Dan
authors.initials: D
authors.lastname: Peters
authors.forename: Thomas
authors.initials: T
authors.lastname: Varming
authors.forename: Claus
authors.initials: C
authors.lastname: Mathiesen
authors.forename: Anders S
authors.initials: AS
authors.lastname: Kristensen
authors.forename: Ulf
authors.initials: U
authors.lastname: Madsen
mesh_terms: D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D018690:Excitatory Amino Acid Agonists; D006801:Humans; D007555:Isoxazoles; D051379:Mice; D009127:Muscle Rigidity / Q000139:chemically induced / Q000188:drug therapy; D018408:Patch-Clamp Techniques; D011422:Propionates; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D001565:Benzoates; D018690:Excitatory Amino Acid Agonists; D007555:Isoxazoles; D011422:Propionates; D018092:Kainic Acid Receptors; D014508:Urea; C081662:alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate