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

Abstract

Affinities of a series of substituted imidazobenzodiazepines at recombinant alpha1beta3gamma2, alpha2beta3gamma2, alpha3beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2 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 alpha5-containing receptor isoform. For example, ligand 27 (RY-023) demonstrated a 55-fold higher selectivity at alpha5beta3gamma2 isoforms in comparison to other receptor subtypes. The affinity ratio of alpha1 (the most prevalent subtype in the brain) to alpha5 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 alpha1, alpha2, alpha3, alpha5, and alpha6 subtypes. A CoMFA regression analysis was applied to predict the ratio of Ki alpha1/Ki alpha5, an index for the selectivity of a ligand at the alpha5 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 alpha1/Ki alpha5, which demonstrated their potential for prediction.

Proximity-accelerated Chemical Coupling Reaction in the Benzodiazepine-binding Site of γ-Aminobutyric Acid Type A Receptors

“…This compound has been described as a positive allosteric modulator with a K i value of 34 nM (41). A model based on quantitative structure/activity relationships developed by Huang et al (11) proposed only a partial superposition of diazepam with the imidazobenzodiazepine RY-80, which carries an acetylenic group instead of the azide group of Ro15-4513, to satisfy a putative common hydrogen donor site. However, the same condition can also be met if the alignment is assumed to be precise, and the protein is allowed to change conformation.…”

Docking of 1,4-Benzodiazepines in the α1/γ2GABAAReceptor Modulator Site

“…Previous attempts have been made to superimpose the structures of allosteric modulators to construct a pharmacophore model for the BZD recognition site (Borea et al, 1987;Villar et al, 1989;Schove et al, 1994;Zhang et al, 1995;Huang et al, 1998Huang et al, , 1999He et al, 2000;Marder et al, 2001;Verli et al, 2002). However, such models are difficult to relate to receptor structure.…”

Pharmacophore models for GABAAmodulators: implications in CNS drug discovery

“…Cook also carried out CoMFA-based 3D QSAR studies on a series of substituted imidazobenzodiazepines using affinity values reported for the recombinant a 1 b 3 g 2 , a 2 b 3 g 2 , a 3 b 3 g 2 , a 5 b 3 g 2 , and a 6 b 3 g 2 GABA A /BZ receptor subtypes to deduce predictive pharmacophore models [85]. Inspection of these models suggested that L 2 site within the pharmacophore/receptor model of the a 1 b 3 g 2 receptor subtype corresponds to the region occupied by a C-8 substituent in [11] CL-218,872 (K i = 57 nM at α1) [11] the unified pharmacophore/receptor model.…”