Predictive Models for GABAA/Benzodiazepine Receptor Subtypes: Studies of Quantitative Structure−Activity Relationships for Imidazobenzodiazepines at Five Recombinant GABAA/Benzodiazepine Receptor Subtypes [αxβ3γ2 (x = 1−3, 5, and 6)] via Comparative Molecular Field Analysis

Publisher Website
Google Scholar
Abstract
Affinities of a series of substituted imidazobenzodiazepines at recombinant α1β3γ2, α2β3γ2, α3β3γ2, α5β3γ2, and α6β3γ2 GABAA/benzodiazepine receptor subtypes are reported. Many of these ligands displayed high affinities (low-nanomolar to subnanomolar scale) at all five receptor subtypes. Furthermore, a number of imidazobenzodiazepines exhibited relatively good selectivity at the α5-containing receptor isoform. For example, ligand 27 (RY-023) demonstrated a 55-fold higher selectivity at α5β3γ2 isoforms in comparison to other receptor subtypes. The affinity ratio of α1 (the most prevalent subtype in the brain) to α5 of this series of ligands ranged from 60- to 75-fold for the most selective ligands. Studies of quantitative structure−activity relationships (QSAR) by means of comparative molecular field analysis (CoMFA) were carried out. As a result, examination of CoMFA models for all five receptor subtypes demonstrated their predictability for affinities of imidazobenzodiazepines at the five receptor subtypes. Regions of molecular fields which would favor or disfavor the binding affinity of a ligand at a specific receptor subtype were examined via CoMFA for α1, α2, α3, α5, and α6 subtypes. A CoMFA regression analysis was applied to predict the ratio of Ki α1/Ki α5, an index for the selectivity of a ligand at the α5 subtype. All of the CoMFA models offered good cross-validated correlations for the ligands in the test set as well as the ratios of Ki α1/Ki α5, which demonstrated their potential for prediction.