Synthesis, biological evaluation and molecular modeling study of thiadiazolo[3,2-a][1,3]diazepine analogues of HIE-124 as a new class of short acting hypnotics.

A new series of 6,7-dihydro-[1,3,4]thiadiazolo[3,2-a][1,3]diazepine analogues were synthesized, and biological evaluated. Compound GS-62 (33) exhibited potent in vivo short acting hypnotic activity with onset time, duration of sleep and therapeutic index of 6.4 ± 0.2, 94.8 ± 5.3 min, 6.62, respectively), in comparison to thiopental sodium (6). Compounds 33 did not show any sign of acute tolerance reported with the maintenance dose of 6. Meanwhile 33 potentiated the in vivo hypnotic effect of 6 in an equimolar amounts (0.06 mmol) combination showing an onset and duration of 7.5 ± 1.3, 62.5 ± 5.9 min, respectively. This combination allowed the use of lower doses of both drugs to avoid the undesirable side effects. Docking studies revealed favorable interactions and binding to BDZ binding site of the GABAA receptor especially with Arg87, Arg149, and Thr151 amino acid residues.