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Thiadiazolodiazepine analogues as a new class of neuromuscular blocking agents: Synthesis, biological evaluation and molecular modeling study.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2017 Jan 27; Vol. 126, pp. 15-23. Date of Electronic Publication: 2016 Sep 30. - Publication Year :
- 2017
-
Abstract
- The synthesis, biological evaluation and molecular modeling study of 6,7-dihydro-[1,3,4] thiadiazolo[3,2-a][1,3]diazepine analogues as new class of neuromuscular blocking agents are described. The new compounds act via competitive mechanism with ACh which could be reversed by the anticholinesterase - Physostigmine. Compounds GS-53 (30) and AAH1 (33) induced dose-dependent neuromuscular blockade with onset time of 3 and 10 min, ED <subscript>50</subscript> 0.15 and 0.36 mmol/kg i.p., respectively, in rats. Compound 30 proved to be as twice as potent as 33 with rapid onset and shorter duration (P < 0.05). Docking profile of 30 and 33 closely resembles HIE-124 (3), in α7β2 nAChR receptor. Molecular modeling analysis indicated that hydrogen bonding to Thr120 and Thr124 beside hydrophobic interactions play effective role incorporating the active ligands to nAChR. The obtained model could be useful for further development of new skeletal muscle relaxants.<br /> (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Acetylcholinesterase chemistry
Acetylcholinesterase metabolism
Animals
Chemistry Techniques, Synthetic
Chickens
Male
Neuromuscular Blocking Agents chemistry
Neuromuscular Blocking Agents metabolism
Protein Conformation
Rats
Thiadiazoles chemistry
Thiadiazoles metabolism
Drug Design
Molecular Docking Simulation
Neuromuscular Blocking Agents chemical synthesis
Neuromuscular Blocking Agents pharmacology
Thiadiazoles chemical synthesis
Thiadiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 126
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 27744183
- Full Text :
- https://doi.org/10.1016/j.ejmech.2016.09.096