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 (Ki 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. α 2β2γ2, and α5β 3γ2 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.
Refinement of the Benzodiazepine Receptor Site Topology by Structure-Activity Relationships of New N-(Heteroarylmethyl)indol-3-ylglyoxylamides
DA SETTIMO PASSETTI, FEDERICO;MARINI, ANNA MARIA;TALIANI, SABRINA;LA MOTTA, CONCETTINA;SIMORINI, FRANCESCA;MARTINI, CLAUDIA
2006-01-01
Abstract
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 (Ki 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. α 2β2γ2, and α5β 3γ2 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
