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.