Rationalizing the binding and a subtype selectivity of synthesized imidazodiazepines and benzodiazepines at GABAA receptors by using molecular docking studies

The pharmacological actions exerted by benzodiazepines are dependent on the discrete alpha protein subunits of the gamma-aminobutyric acid type A receptor (GABA(A) R). Recent developments via a cryo-EM structure of the alpha 1133 gamma 2L GABA(A) R ion channel provide crucial insights into ligand efficacy and binding affinity at this subtype. We investigated the molecular interactions of diazepam and alprazolam bound GABA(A) R structures (6HUP and 6HUO) to determine key binding interaction domains. A halogen bond between the chlorine atoms of diazepam and alprazolam with the group on the backbone of the alpha 1 histidine amino acid 102 is important to the positive allosteric modulatory actions of diazepam and alprazolam in the alpha 1133 gamma 2L GABA(A) R ion channel. In order to gain insight into alpha subtype selectivity we designed and synthesized close structural analogs of diazepam and alprazolam. These compounds were then docked into the recently publish cryo-EM structures of GABA(A) Rs (6HUP and 6HUO). This modeling along with radio-ligand binding data resulted in the conclusion that the non-classical bioisosteric replacement of the chlorine atom at C7 with an ethinyl group (compound 5) resulted in an 11-fold gain in alpha 5 binding selectivity over the alpha 1 subtype. Moreover, the potency of compound 5 resulted in a ligand with less sedation than diazepam, while still maintaining the same anxiolytic potency. These modeling data extend our understanding of the structural requirements for alpha-subtype-selective compounds that can be utilized to achieve improved medical treatments. It is clear that the ethinyl group in place of a halogen atom decreases the affinity and efficacy of benzodiazepines and imidazodiazepines at alpha 1 subtypes, which results in less sedation and ataxia.

Automated summary

This study investigates the pharmacological actions of benzodiazepines on the GABA(A) receptor and reveals key binding interaction domains through cryo-EM structure analysis. By designing and synthesizing structural analogs, compounds with improved efficacy and selectivity were discovered. Modeling and binding data demonstrate the potential of these compounds for improved medical treatments.