Rationalizing the binding and α 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 α protein subunits of the γ-aminobutyric acid type A receptor (GABA R). Recent developments via a cryo-EM structure of the α1β3γ2L GABA 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 R structures (6HUP and 6HUO) to determine key binding interaction domains.

Improved scale-up synthesis and purification of clinical asthma candidate MIDD0301.

We report an improved and scalable synthesis of MIDD0301, a positive GABA receptor modulator that is under development as oral and inhaled treatments for asthma. In contrast to other benzodiazepines in clinical use, MIDD0301 is a chiral compound that has limited brain absorption. The starting material to generate MIDD0301 is 2-amino-5-bromo-2'-fluorobenzophenone, which has a non-basic nitrogen due to electron withdrawing substituents in the and positions, reducing its reactivity towards activated carboxylic acids.