Benzimidazole‐type Glycine Antagonists: The Role of the Ring Nitrogen Atoms

Several derivatives of 1 H ‐benzimidazole‐2‐carboxylic acid (BICA, 2a ) were tested in vitro in comparison to 1 H ‐indole‐2‐carboxylic acid (ICA, 1e ) for their ability to displace [ 3 H]glycine from rat hippocampal membranes. Compound 2a was 8 times more potent than 1e ( K i 5.3 μM, as compared to 42 μM). 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 [ 3 H]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.