2-arylureidobenzoic acids: selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
2-arylureidobenzoic acids : selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5. / Valgeirsson, Jon; Nielsen, Elsebet Ø; Peters, Dan; Varming, Thomas; Mathiesen, Claus; Kristensen, Anders S; Madsen, Ulf.
In: Journal of Medicinal Chemistry, Vol. 46, No. 26, 18.12.2003, p. 5834-43.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - 2-arylureidobenzoic acids
T2 - selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5
AU - Valgeirsson, Jon
AU - Nielsen, Elsebet Ø
AU - Peters, Dan
AU - Varming, Thomas
AU - Mathiesen, Claus
AU - Kristensen, Anders S
AU - Madsen, Ulf
PY - 2003/12/18
Y1 - 2003/12/18
N2 - 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.
AB - 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.
KW - Animals
KW - Benzoates
KW - Cell Line
KW - Excitatory Amino Acid Agonists
KW - Humans
KW - Isoxazoles
KW - Mice
KW - Muscle Rigidity
KW - Patch-Clamp Techniques
KW - Propionates
KW - Quantitative Structure-Activity Relationship
KW - Radioligand Assay
KW - Receptors, Kainic Acid
KW - Urea
U2 - 10.1021/jm030428j
DO - 10.1021/jm030428j
M3 - Journal article
C2 - 14667236
VL - 46
SP - 5834
EP - 5843
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 26
ER -
ID: 156345161