Prospects for the use of 3-R-benzo[f][1,2,4]triazino[2,3-d][1,4]diazepine-2,7(6H,8H)-diones as agonists and antagonists of GABAA receptors
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Purpose The benzo[ f ][1,2,4]triazino[2,3- d ][1,4]diazepine-2,7(6 H ,8 H )-dione scaffold combines features of classical 1,4-benzodiazepines and β-carboline inverse agonists, and was therefore examined at the γ-aminobutyric acid type A receptor (GABA A R) benzodiazepine (BZD) modulatory site. Methods Blind docking of 47 derivatives was performed against eight human GABA A R cryo-EM structures spanning the BZD-site pharmacological spectrum, together with ADMET profiling (SwissADME, ProTox-3.0). Synthetically accessible members of series 1 were then evaluated in vivo in the thiopental-induced sleep test and in a predator-odour model of post-traumatic stress disorder (PTSD), with determination of cytosolic brain GABA and serotonin transporter (Slc6a4) concentrations. Results At the α1-containing structures, all C-3 aryl compounds exceeded the predicted BZD-site affinity of the co-crystallized references diazepam, flumazenil and DMCM. A C-3 aryl substituent appeared necessary for productive BZD-site engagement, improving the docking score by 1.9 kcal/mol in the matched pair 5.4 / 1.11 ; the 3,4-dimethylphenyl group conferred the highest mean α1 affinity (compound 1.6 , − 10.6 kcal/mol), whereas 11-chloro substitution favored both affinity and BZD-site selectivity (compound 1.11 , − 10.9 kcal/mol; Δ = −2.8 kcal/mol). Docking at α5 constructs indicated incipient α1/α5 selectivity governed primarily by the C-3 substituent. The test compounds satisfied the Veber and Egan criteria and generated no PAINS alerts. Five members of series 1 prolonged thiopental-induced sleep (+ 30.6% to + 72.2%); compounds 1.5 and 1.7 also shortened sleep-onset latency and exceeded diazepam on both parameters. In the PTSD model, stress reduced brain GABA 3.65-fold; compound 1.5 restored this concentration to a level statistically indistinguishable from intact animals and exceeded diazepam. All compounds except 1.1 increased Slc6a4 content, an effect that diazepam did not produce. Conclusion These computational and preliminary in vivo findings support the benzotriazinodiazepinedione scaffold as a chemotype at the GABA A R benzodiazepine site, identify compounds 1.5 and 1.6 as the leads within the synthesized series, and define the subtype-resolved characterization required to establish the mechanism.
