Bioisosteric modifications of 2-arylureidobenzoic acids: selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5

TY - JOUR

T1 - Bioisosteric modifications of 2-arylureidobenzoic acids

T2 - selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5

AU - Valgeirsson, Jon

AU - Nielsen, Elsebet O

AU - Peters, Dan

AU - Mathiesen, Claus

AU - Kristensen, Anders S

AU - Madsen, Ulf

PY - 2004/12/30

Y1 - 2004/12/30

N2 - 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 IC(50) values of 1.5 and 2.0 muM, respectively, compared to compound 2a with IC(50) = 4.8 muM). 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.

AB - 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 IC(50) values of 1.5 and 2.0 muM, respectively, compared to compound 2a with IC(50) = 4.8 muM). 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.

KW - Animals

KW - Benzoates

KW - Dose-Response Relationship, Drug

KW - Female

KW - Humans

KW - Mice

KW - Rats

KW - Receptors, Kainic Acid

KW - Structure-Activity Relationship

U2 - 10.1021/jm030638w

DO - 10.1021/jm030638w

M3 - Journal article

C2 - 15615543

SN - 0022-2623

VL - 47

SP - 6948

EP - 6957

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 27

ER -