Skip to main content
SpringerLink
Log in

New and mild method for the synthesis of alprazolam and diazepam and computational study of their binding mode to GABAA receptor

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

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, 1H NMR and 13C NMR. Three-dimensional (3D) model of GABAA was constructed using X-ray crystal structure of homopentameric caenorhabditis elegans glutamate-gated chloride channel (GluCl) (3RHW) at 3.3 Å 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Albaugh PA, Marshall L, Gregory J, White G, Hutchison A, Ross PC, Gallagher DW, Tallman JF, Crago M, Cassella JV (2002) Synthesis and biological evaluation of 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimdin-5(6H)-ones as functionally selective ligands of the benzodiazepine receptor site on the GABAA receptor. J Med Chem 45:5043–5051

    Article  CAS  PubMed  Google Scholar 

  • Altschul SF, Madden TL, Schaffer AA, Zhang JH, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barnard EA, Skolnick P, Olwen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ (1998) International Union of Pharmacology. XV. Subtypes of γ-aminobutyric acidA receptors. Classification on the basis of subunit structure and receptor function. Pharmacol Rev 50:291–313

    CAS  PubMed  Google Scholar 

  • Barthel A, Trieschmann L, Ströhl D, Kluge R, Böhm G, Csuk R (2009) Synthesis of dimeric quinazolin-2-one, 1,4-benzodiazepin-2-one, and isoalloxazine compounds as inhibitors of amyloid peptides association. Arch Pharm 342(8):445–452

    Article  CAS  Google Scholar 

  • Baumann M, Baxendale IR, Ley SV, Nikbin N (2011) An overview of the key routes to the best-selling 5-membered ring heterocyclic pharmaceuticals. Beilstein J Org Chem 7:442–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berendsen HJC, Van der Spoel D, Drunen RV (1995) GROMACS: a message-passing parallel molecular dynamics implementation. Comput Phys Commun 91:43–56

    Article  CAS  Google Scholar 

  • Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bolli MH, Marfurt J, Grisostomi C, Boss C, Binlcert C, Hess P, Treiber E, Thorin A, Morrison K, Buchmann S, Bur D, Ramuz H, Clozel M, Fischli W, Weller T (2004) Novel benzo[1,4]diazepin-2-one derivatives as endothelin receptor antagonists. J Med Chem 47:2776–2795

    Article  CAS  PubMed  Google Scholar 

  • Cortez-Maya S, Cortes EC, Hernández-Ortega S et al (2012) Synthesis of 2-aminobenzophenone derivatives and their anticancer activity. Synth Commun 42:46–54

    Article  CAS  Google Scholar 

  • Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N·log(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092

    Article  CAS  Google Scholar 

  • Doss SH, Baghos VB, Abdelhamid AO, Halim MMA (2000) Synthesis of Sultam derivatives with expected biological activity. 15. J Mol 6:816–822

    Article  Google Scholar 

  • Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8593

    Article  CAS  Google Scholar 

  • Farrar SJ, Whiting PJ, Bonnert TP, McKernan RM (1999) Stoichiometry of a ligand-gated ion channel determined by fluorescence energy transfer. J Biol Chem 274:10100–10104

    Article  CAS  PubMed  Google Scholar 

  • Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Zakrzewski VG, Montgomery JA, Stratmann RE, Burant JC, Dapprich S, Millam JM, Daniels AD, Kudin KN, Strain MC, Farkas O, Tomasi J, Barone V, Cossi M, Cammi R, Mennucci B, Pomelli C, Adamo C, Clifford S, Ochterski J, Petersson GA, Ayala PY, Cui Q, Morokuma K, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Cioslowski J, Ortiz JV, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Gomperts R, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Gonzalez C, Challacombe M, Gill PMW, Johnson BG, Chen W, Wong MW, Andres JL, Head-Gordon M, Replogle ES, Pople JA (2003) Gaussian 03. Gaussian, Wallingford, CT

    Google Scholar 

  • Granger RE, Campbell EL, Johnston GAR (2005) (+)- and (−)-borneol: efficacious positive modulators of GABA action at human recombinant α1 β2 γ 2L GABAA receptors. Biochem Pharmacol 69:1101–1111

    Article  CAS  PubMed  Google Scholar 

  • Grant JAA, Bonnick T, Gossell-Williams M, Clayton T, Cook JM, Jackson YA (2010) Synthesis, pharmacological studies and molecular modeling of some tetracyclic 1,3-diazepinium chlorides. Bioorg Med Chem 18:909–921

    Article  CAS  PubMed  Google Scholar 

  • Griffin CE, Kaye AM, Rivera Bueno F, Kaye AD (2013) Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J 13(2):214–223

    PubMed  PubMed Central  Google Scholar 

  • Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38

    Article  CAS  PubMed  Google Scholar 

  • Jackson B, Hester J (1980) Novel synthesis of the pharmacologically important 1-substituted-6-phenyl-4H-s-triazolo[4,3-α][1,4]benzodiazepines. J Heterocycl Chem 17(3):575–581

    Article  Google Scholar 

  • Lindahl E, Hess B, van der Spoel D (2001) GROMACS 3.0: a package for molecular simulation and trajectory analysis. J Mol Model 7:306–317

    CAS  Google Scholar 

  • Liou JP, Chang YL, Kuo FM, Chang CW, Tseng HY, Wang CC, Yang YN, Chang JY, Lee SJ, Hsieh HP (2004) Concise synthesis and structure–activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents. J Med Chem 47:4247–4257

    Article  CAS  PubMed  Google Scholar 

  • Mendonça Júnior FJB, Scotti L, Ishiki H, Botelho SPS, Da Silva MS, Scotti MT (2015) Benzo-and thienobenzo-diazepines: multi-target drugs for CNS disorders. Mini-Rev Med Chem 15:630–647

    Article  PubMed  Google Scholar 

  • Mokrab Y, Bavro VN, Mizuguchi K, Todorov NP, Martin IL, Dunn SMJ, Chan SL, Chau PL (2007) Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor. J Mol Gr Model 26:760–774

    Article  CAS  Google Scholar 

  • Nayeem N, Green TP, Martin IL, Barnard EA (1994) Quaternary structure of the native GABAA receptor determined by electron microscopic image analysis. J Neurochem 62:815–818

    Article  CAS  PubMed  Google Scholar 

  • Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G (2000) GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101:815–850

    Article  CAS  PubMed  Google Scholar 

  • Renard S, Olivier A, Granger P, Avenet P, Graham D, Sevrin M, George P, Besnard F (1999) Structural elements of γ-aminobutyric acid type A receptor conferring subtype selectivity for benzodiazepine site ligands. J Biol Chem 274:13370–13374

    Article  CAS  PubMed  Google Scholar 

  • Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815

    Article  CAS  PubMed  Google Scholar 

  • Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461

    CAS  PubMed  PubMed Central  Google Scholar 

  • Usui Y, Yukio H, Mikami I, Masuda T (1970) Benzodiazepines. I. Syntheses of new 1,4-benzodiazepine derivatives. Takeda Kenkyusho Ho 29(1):145–152

    CAS  Google Scholar 

  • Van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718

    Article  Google Scholar 

  • Van Gunsteren WF, Billeter SR, Eising AA, Huenberger PH, Kruger P, Mark AE, Scott WRP, Tironi IG (1996) Biomolecular simulation the GROMOS 96 manual and user guide, Switzerland

  • Vijayan RSK, Bhattacharyya D, Ghoshal N (2012) Deciphering the binding mode of Zolpidem to GABAA α1 receptor—insights from molecular dynamics simulation. J Mol Model 18:1345–1354

    Article  CAS  PubMed  Google Scholar 

  • Wallace AC, Laskowski RA, Thornton JM (1995) LIGPLOT: a program to generate schematic diagrams of protein–ligand interactions. Protein Eng 8:127–134

    Article  CAS  PubMed  Google Scholar 

  • Wieland HA, Luddens H, Seeburg PH (1992) A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. J Biol Chem 267:1426–1429

    CAS  PubMed  Google Scholar 

  • Zhu Q, Vaughn MW (2005) Surface tension effect on transmembrane channel stability in a model membrane. J Phys Chem 109:19474–19483

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We appreciate financial support of Shahreza Branch, Islamic Azad University (IAUSH) Research Council.

Author information

Authors and Affiliations

  1. Department of Chemistry, Shahreza Branch, Islamic Azad University, Shahreza, Isfahan, 86145-311, Iran

    Ahmad R. Massah, Hamid Ardeshiri Lordejani & Nahad Asakere

  2. Razi Chemistry Research Center, Islamic Azad University, Shahreza Branch, Shahreza, Isfahan, 86145-311, Iran

    Ahmad R. Massah

  3. Department of Bioinformatics, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran

    Sajjad Gharaghani

Authors
  1. Ahmad R. Massah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sajjad Gharaghani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hamid Ardeshiri Lordejani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nahad Asakere
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ahmad R. Massah.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Massah, A.R., Gharaghani, S., Lordejani, H.A. et al. New and mild method for the synthesis of alprazolam and diazepam and computational study of their binding mode to GABAA receptor. Med Chem Res 25, 1538–1550 (2016). https://doi.org/10.1007/s00044-016-1585-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-016-1585-z

Keywords

Search

Navigation