Bioisosteric Modifications of 2-Arylureidobenzoic Acids:  Selective Noncompetitive Antagonists for the Homomeric Kainate Receptor Subtype GluR5

• Published in: Journal of medicinal chemistry Vol. 47; no. 27; pp. 6948 - 6957
• Main Authors: Valgeirsson, Jon, Nielsen, Elsebet Ø, Peters, Dan, Mathiesen, Claus, Kristensen, Anders S, Madsen, Ulf
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 30.12.2004; Amer Chemical Soc
• Subjects: Animals; Benzoates - chemical synthesis; Benzoates - pharmacology; Biological and medical sciences; Chemistry, Medicinal; Dose-Response Relationship, Drug; Female; Glutamatergic system (aspartate and other excitatory aminoacids); Humans; Life Sciences & Biomedicine; Medical sciences; Mice; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Receptors, Kainic Acid - antagonists & inhibitors; Science & Technology; Structure-Activity Relationship; NMDA; DERIVATIVES; GLUTAMATE; Tetrazole derivatives; Electrophysiology; Organic bromine compounds; Glutamate receptor; Selectivity; Organic chlorine compounds; In vitro; Kainate receptor; Benzoic acid derivatives; Structure activity relation; Ureas; Antagonist; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030638w

2-Arylureidobenzoic acids (AUBAs) have recently been presented as the first series of selective noncompetitive GluR5 antagonists. In this paper we have modified the acidic moiety of the AUBAs by introducing different acidic and neutral groups, and similarly, we have replaced the urea linker of the AUBAs with other structurally related linkers. Replacing the acid with neutral substituents led to inactive compounds in all instances, showing that an acidic moiety is necessary for activity. Replacing the carboxylic moiety in 2a with a sulfonic acid (5c) or a tetrazole ring (5d) improved the potency at GluR5 receptors (compounds 5c and 5d showed IC50 values of 1.5 and 2.0 μM, respectively, compared to compound 2a with IC50 = 4.8 μM). Compound 5c did not show improved in vivo activity in the ATPA rigidity test compared to 2a, whereas compound 5d was 4 times more potent than 2a. All compounds wherein the urea linker had been replaced showed lower or no activity. The results described extend the knowledge of structure−activity relationships for the AUBAs, and compound 5d may prove to be a good candidate for studying GluR5 receptors in vitro and in vivo.