From the Pharmacophore to the Homology Model of the Benzodiazepine Receptor: The Indolyglyoxylamides Affair

Barbara      Cosimelli; Sandro      Cosconati; Luciana      Marinelli; Ettore      Novellino; Giovanni      Greco

doi:10.2174/156802612799078702

Abstract

Interaction between the so-called benzodiazepine receptor (BzR) and the chemically heterogeneous class of its ligands is still one of the most challenging objects of theoretical studies. In the mid-90s our group began to collaborate with Prof. Antonio Da Settimo and coworkers to a project of synthesis and biological evaluation of indolylglyoxylamides designed as BzR ligands. Herein we review our efforts in designing these compounds and in interpreting their structureaffinity relationships. Our investigations were carried out for years by adopting the pharmacophore/topological model for BzR ligands set up by Cooks group. In an attempt to rationalize some puzzling structure-affinity relationships we speculated in 1998 that our ligands interact with the BzR by assuming one of two alternative binding modes (called “A” and “B”) depending on whether or not they were substituted at the 5-position of the indole nucleus. Such a model received support from a considerable amount of experimental data accumulated throughout our researches. About a decade later, docking calculations performed on a homology-built model of the 1 BzR subtype were found in agreement with the hypothesis of mode A and mode B of binding accessible to 5-H and, respectively, 5-Cl/NO2 indole derivatives.

Keywords: Benzodiazepine receptors, pharmacophore, molecular modelling, homology modelling, docking, binding modes, synthesis and biological evaluation of indolylglyoxylamides, structureaffinity relationships, homology-built model, 5-Cl/NO2 indole derivatives