Benzimidazole-type glycine antagonists: the role of the ring nitrogen atoms.
Several derivatives of 1H-benzimidazole-2-carboxylic acid (BICA, 2a) were tested in vitro in comparison to 1H-indole-2-carboxylic acid (ICA, 1e) for their ability to displace [3H]glycine from rat hippocampal membranes. Compound 2a was 8 times more potent than 1e (Ki 5.3 microM, as compared to 42 microM). However, introduction of a carboxymethyl group or a corresponding ester at position 3 had no positive effect on the potency of 2a, while this type of structural modification increased the potency of 1e significantly. Nevertheless, 1-carboxymethyl-BICA (2b) displaced [3H]glycine with similar potency as the corresponding 3-carboxymethyl-ICA 1c, indicating that also a nitrogen atom lacking a hydrogen atom can be engaged in glycine receptor interaction. N-Methylation strongly reduced the potencies of both BICA and ICA derivatives.
Berger
M L
ML
Institute of Biochemical Pharmacology, University of Vienna, Wien, Austria.
Schödl
C
C
Noe
C R
CR
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D005998:Glycine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018009:Receptors, Glycine / Q000378:metabolism; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D018009:Receptors, Glycine; D005998:Glycine