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 S₁ 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 S₁ site of the BzR. Compounds 1, 2, 8, 19, 20, and 22, tested at recombinant rat α₁β₂γ₂, α₂β₂γ₂, and α₅β₃γ₂ BzRs, elicited selectivity for the α₁β₂γ₂ isoform. On the basis of published mutagenesis studies and the present SARs, we speculate that the S₁ HBA/D group might be identified as the hydroxyl of α₁-Tyr209 or of other neighboring amino acids.