Refinement of the benzodiazepine receptor site topology by structure-activity relationships of new N-(heteroarylmethyl)indol-3-ylglyoxylamides.

N-(Heteroarylmethyl)indol-3-ylglyoxylamides (1-26) were synthesized and evaluated as ligands of the benzodiazepine receptor (BzR) to probe the hydrogen bonding properties of the so-called S 1 site of the BzR by means of suitable heterocyclic side chains. SARs were developed in light of our hypothesis of binding modes A and B. Pyrrole and furan derivatives adopting mode A (2, 8, 10, 20, 22) turned out to be more potent (K i values < 35 nM) than their analogues lacking hydrogen bonding heterocyclic side chains. These data suggest that the most potent indoles interact with a hydrogen bond acceptor/donor (HBA/D) group located within the S 1 site of the BzR. Compounds 1, 2, 8, 19, 20, and 22, tested at recombinant rat α 1 β 2 γ 2 , α 2 β 2 γ 2 , and α 5 β 3 γ 2 BzRs, elicited selectivity for the α 1 β 2 γ 2 isoform. On the basis of published mutagenesis studies and the present SARs, we speculate that the S 1 HBA/D group might be identified as the hydroxyl of α 1 -Tyr209 or of other neighboring amino acids.