Abstract
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.
Structure of the most active short acting hypnotic GS-62 (33), onset time 6.4 ± 0.2 min, duration of sleep 94.8 ± 5.3 min, and therapeutic index, 6.62. [Display omitted]
•Synthesis of 6,7-dihydro-[1,3,4]thiadiazolo[3,2-a][1,3]diazepines.•Compound GS-62 (33) is a short acting hypnotic.•Compound 33 potentiate the in vivo hypnotic effect of thiopental sodium.•Recognition with Arg87, Arg149 at BDZ binding site essential for activity.•The new compounds exert their action via GABAA agonism.