New and mild method for the synthesis of alprazolam and diazepam and computational study of their binding mode to GABA(A) receptor

作者：Massah Ahmad R^*; Gharaghani Sajjad; Lordejani Hamid Ardeshiri; Asakere Nahad

来源：Medicinal Chemistry Research, 2016, 25(8): 1538-1550.

DOI：10.1007/s00044-016-1585-z

• Alprazolam
• Diazepam
• GABA
• Homology modeling
• Molecular docking
• Molecular dynamics simulation

A new method for the synthesis of 8-chloro-1-methyl-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (alprazolam) and 7-chloro-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (diazepam) from 2-amino-5-chloro benzophenone was described under mild conditions. Most of the synthetic steps were carried out under solvent-free conditions, and the products were obtained in high yield and purity. The products were characterized by comparison of physical properties with authentic samples and also by IR, H-1 NMR and C-13 NMR. Three-dimensional (3D) model of GABA(A) was constructed using X-ray crystal structure of homopentameric caenorhabditis elegans glutamate-gated chloride channel (GluCl) (3RHW) at 3.3 as the template based on sequence comparison and homology modeling method. The homology modeling and MD simulation studies predicted the 3D structure of receptor in a water environment. The resulted conformation of the receptor was used for docking of the alprazolam and diazepam. Docking studies indicated many important interactions of the drugs with the receptor. Furthermore, the complex of GABA with drugs was used in MD simulation to realize the conformation changes of the complex.

• 出版日期2016-8