title: Benzimidazoles as NMDA glycine-site antagonists: study on the structural requirements in 2-position of the ligand.
abstract: A series of different substituted benzimidazole derivatives has been synthesized and evaluated for the ability to displace [3H]MDL-105,519 to rat cortical membranes. Two benzimidazole-2-carboxylic acids 9 b and 9 c, in this substitution pattern not yet described as glycine antagonists, showed IC50 values of 0.89 microM (9 b) and 38.0 microM (9 c). Replacement of the carboxylate function in 2-position by a sulfonic acid moiety appreciably increased solubility, but decreased the affinity giving evidence for the strong need of the carboxylate group within the ligand. Further structure-activity studies using benzimidazole-2-one derivatives with an acetic acid moiety adjacent to a ring nitrogen revealed new insights into the importance of amide functionalities within the heterocycle for the affinity of antagonist glycine-site ligands.
authors.affiliation: Department of Pharmacy, Johannes Gutenberg University, Mainz, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Dannhardt
authors.forename: B K
authors.initials: BK
authors.lastname: Kohl
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry* / Q000494:pharmacology; D005998:Glycine / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; C101788:MDL 105519; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine