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*

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Date
2016-08-22Author
I. El-Subbagh a, Hussein
S. Hassan, Ghada
E.H. El-Taher, Kamal
M. El-Messery, Shahenda
S. Al-Azab, Adel
A.-M. Abdelaziz, Alaa
M. Hefnawy, Mohamed
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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.
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