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A computational study on phenibut lactamization mechanism and the pH effects on the process

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Abstract

The current work investigates the lactamization reaction of neuropsychotropic medicine phenibut to higher toxicity phenibut-lactam. The reaction is considered as an intramolecular cyclization which finally leads to generation of phenibut-lactam component. Herein, we considered three different structural forms for the chemically intact phenibut which consist of two stable R1, R2, and a relatively distorted isomer R*. The initial stage in this reaction is the transformation of two stable isomers into the unstable form, R*. The calculations showed that there is a transition state (TS) close to the unstable geometry, R*. This transition state possesses 31.30 kcal/mol more energy compared to the isomer R* (5.98 kcal/mol). By studying the thermodynamic stability of the lactam structure (− 13.55 kcal/mol), we can clearly conclude that pheni-l component has higher thermal stability compared to its related phenibut. Also, from the investigation of this reaction in various pH, it was found that the rate of reaction reduces under both basic and acidic conditions.

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Notes

  1. All analyses shown in the text were done using the the B3LYP-D3 level except mentioned otherwise.

References

  1. Lapin I (2001) Phenibut (β-Phenyl-GABA): a tranquilizer and nootropic drug. CNS Drug Rev 7:471–481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Khaunina R (1964) Tranquilizing effects of beta-phenyl-gamma-aminobutyric acid (FENIGAM). Biulleten’eksperimental’noi Biol Med 57:54

    CAS  Google Scholar 

  3. Khaunina R, Lapin I (1989) Use of fenibut in psychiatry and neurology and its place among other psychotropic drugs (review of the literature). Zhurnal nevropatologii i psikhiatrii imeni SS Korsakova (Moscow, Russia: 1952), 89: 142.

  4. Sytinsky I, Soldatenkov A, Lajtha A (1978) Neurochemical basis of the therapeutic effect of γ-aminobutyric acid and its derivatives. Prog Neurobiol 10:89–133

    Article  CAS  PubMed  Google Scholar 

  5. Perfilova V, Tiurenkov I, Berestovitskaia V, Vasil’eva O (2006) Cardioprotective effect of GABA derivatives in acute alcohol intoxication. Eksperimental’naia i klinicheskaia farmakologiia 69:23–27

    PubMed  CAS  Google Scholar 

  6. Tyurenkov I, Perfilova V, Popova T, Ivanova L, Prokofiev I, Gulyaeva O, Stepa L (2013) Changes in oxidant and antioxidant status of females with experimental gestosis under the effect of GABA derivatives. Bull Exp Biol Med 2013:155

    Google Scholar 

  7. Dambrova M, Zvejniece L, Liepinsh E, Cirule H, Zharkova O, Veinberg G, Kalvinsh I (2008) Comparative pharmacological activity of optical isomers of phenibut. Eur J Pharmacol 583:128–134

    Article  CAS  PubMed  Google Scholar 

  8. Zvejniece L, Vavers E, Svalbe B, Veinberg G, Rizhanova K, Liepins V, Kalvinsh I, Dambrova M (2015) R-phenibut binds to the α2–δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects. Pharmacol Biochem Behav 137:23–29

    Article  CAS  PubMed  Google Scholar 

  9. Bowery NG (2006) GABAB receptor: a site of therapeutic benefit. Curr Opin Pharmacol 6:37–43

    Article  CAS  PubMed  Google Scholar 

  10. Ziablitseva E, Pavlova I (2007) Effect of GABA receptor agonist phenibut on behavior and respiration of rabbits in the negative emotional situation. Zhurnal vysshei nervnoi deiatelnosti imeni IP Pavlova 57:479–488

    CAS  Google Scholar 

  11. Owen DR, Wood DM, Archer JR, Dargan PI (2016) Phenibut (4-amino-3-phenyl-butyric acid): availability, prevalence of use, desired effects and acute toxicity. Drug Alcohol Rev 35:591–596

    Article  PubMed  Google Scholar 

  12. Calandre EP, Rico-Villademoros F, Slim M (2016) Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use. Expert Rev Neurother 16:1263–1277

    Article  CAS  PubMed  Google Scholar 

  13. Eroglu C, Allen NJ, Susman MW, O’Rourke NA, Park CY, Özkan E, Chakraborty C, Mulinyawe SB, Annis DS, Huberman AD (2009) Gabapentin receptor α2δ-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 139:380–392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zong Z, Desai SD, Kaushal AM, Barich DH, Huang HS, Munson EJ, Suryanarayanan R, Kirsch LE (2011) The stabilizing effect of moisture on the solid-state degradation of gabapentin. AAPS PharmSciTech 12:924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zour E, Lodhi SA, Nesbitt RU, Silbering SB, Chaturvedi PR (1992) Stability studies of gabapentin in aqueous solutions. Pharm Res 9:595–600

    Article  CAS  PubMed  Google Scholar 

  16. Hadidi S, Shiri F, Norouzibazaz M (2020) Mechanistic study of fenoprofen photoisomerization to pure (S)-fenoprofen: a DFT study. Struct Chem 31:115–122

    Article  CAS  Google Scholar 

  17. Hadidi S, Shiri F, Norouzibazaz M (2019) Conversion mechanism and isomeric preferences of the cis and trans isomers of anti-cancer medicine carmustine. A double hybrid DFT calculation. Chem Phys 522:39–43

    Article  CAS  Google Scholar 

  18. Hadidi S, Shiri F, Norouzibazaz M (2019) A theoretical survey of the ability of nanocarbon layers to deliver anti-cancer drug temozolomide to the target cancer cells. Curr Chem Lett 8:53–62

    Article  Google Scholar 

  19. Parr RG (1980) Density functional theory of atoms and molecules. In: Horizons of quantum chemistry. Springer, Dordrecht, pp 5–15

    Google Scholar 

  20. Burke K (2012) Perspective on density functional theory. ‎J Chem Phys 136:150901

    Article  CAS  PubMed  Google Scholar 

  21. Montgomery JA Jr, Frisch MJ, Ochterski JW, Petersson GA (1999) A complete basis set model chemistry. VI. Use of density functional geometries and frequencies. J Chem Phys 110:2822–2827

    Article  CAS  Google Scholar 

  22. Montgomery JA Jr, Frisch MJ, Ochterski JW, Petersson GA (2000) A complete basis set model chemistry. VII. Use of the minimum population localization method. J Chem Phys 112:6532–6542

    Article  CAS  Google Scholar 

  23. Elstner M, Hobza P, Frauenheim T, Suhai S, Kaxiras E (2001) Hydrogen bonding and stacking interactions of nucleic acid base pairs: a density-functional-theory based treatment. J Chem Phys 114:5149–5155

    Article  CAS  Google Scholar 

  24. Grimme S, Antony J, Ehrlich S, Krieg H (2010) A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J Chem Phys 132:154104

    Article  CAS  PubMed  Google Scholar 

  25. Grimme S (2006) Semiempirical hybrid density functional with perturbative second-order correlation. J Chem Phys 124:034108

    Article  CAS  PubMed  Google Scholar 

  26. Zahedi E, Shaabani S, Shiroudi A (2017) Following the molecular mechanism of decarbonylation of unsaturated cyclic ketones using bonding evolution theory coupled with NCI analysis. J Phys Chem A 121:8504–8517

    Article  CAS  PubMed  Google Scholar 

  27. Li X, Frisch MJ (2006) Energy-represented direct inversion in the iterative subspace within a hybrid geometry optimization method. J Chem Theory Comput 2:835–839

    Article  CAS  PubMed  Google Scholar 

  28. Fukui K (1981) The path of chemical reactions-the IRC approach. Acc Chem Res 14:363–368

    Article  CAS  Google Scholar 

  29. Hratchian H, Schlegel H (2005) Theory and applications of computational chemistry: the first 40 years, Dykstra, CE, pp. 195-249.

  30. Marenich AV, Cramer CJ, Truhlar DG (2009) Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J Phys Chem B 113:6378–6396

    Article  CAS  PubMed  Google Scholar 

  31. Barone V, Cossi M (1998) Quantum calculation of molecular energies and energy gradients in solution by a conductor solvent model. J Phys Chem A 102:1995–2001

    Article  CAS  Google Scholar 

  32. Cossi M, Rega N, Scalmani G, Barone V (2003) Energies, structures, and electronic properties of molecules in solution with the C-PCM solvation model. J Comput Chem 24:669–681

    Article  CAS  PubMed  Google Scholar 

  33. Lu T, Chen F (2012) Atomic dipole moment corrected Hirshfeld population method. J Theor Comput Chem 11:163–183

    Article  CAS  Google Scholar 

  34. Neese F (2009) Orca, An Ab Initio, DFT and semiempirical electronic structure package, p. 3.

  35. Shiri F, Norouzibazaz M, Yari A, Taherpour AA (2018) A DFT study of both the hydrolytic degradation and protonation of semustine in variation conditions of pH and interaction of drug with DNA nucleobases. Struct Chem 29:1465–1474

    Article  CAS  Google Scholar 

  36. Hadidi S, Shiri F, Norouzibazaz M (2019) A DFT study of the degradation mechanism of anticancer drug carmustine in an aqueous medium. Struct Chem 30:1315–1321

    Article  CAS  Google Scholar 

  37. Verma AM, Kishore N (2018) Kinetics of decomposition reactions of acetic acid using DFT approach. Open Chem Eng J 2018:12

    Google Scholar 

  38. Jong UG, Yu CJ, Ri GC, McMahon AP, Harrison NM, Barnes PR, Walsh A (2018) Influence of water intercalation and hydration on chemical decomposition and ion transport in methylammonium lead halide perovskites. J Mate Chem A 6:1067–1074

    Article  CAS  Google Scholar 

  39. Brea O, Daver H, Rebek J Jr, Himo F (2019) Mechanism (s) of thermal decomposition of N-Nitrosoamides: a density functional theory study. Tetrahedron 75:929–935

    Article  CAS  Google Scholar 

  40. Chen CS, Shieh WR, Lu PH, Harriman S, Chen CY (1991) Metabolic stereoisomeric inversion of ibuprofen in mammals. Biochim Biophys Acta (BBA)-Protein Struct Mol Enzymol 1078:411–417

    Article  CAS  Google Scholar 

  41. Zong Z, Qiu J, Tinmanee R, Kirsch LE (2012) Kinetic model for solid-state degradation of gabapentin. J Pharm Sci 101:2123–2133

    Article  CAS  PubMed  Google Scholar 

  42. Huang PQ, Huang YH, Geng H, Ye JL (2016) Metal-free C–H alkyliminylation and acylation of alkenes with secondary amides. Sci Rep 6:1–10

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran, and the Research and Computational Lab of Theoretical Chemistry and Nano Structures of Razi University Kermanshah-Iran.

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Authors and Affiliations

  1. Department of Inorganic Chemistry, Faculty of Chemistry, Razi University, Kermanshah, Iran

    Saba Hadidi & Farshad Shiri

  2. Department of Nano Chemistry, Faculty of Chemistry, Razi University, Kermanshah, Iran

    Mohammadsaleh Norouzibazaz

  3. Department of Organic Chemistry, Faculty of Chemistry, Razi University, Kermanshah, Iran

    Mohammadsaleh Norouzibazaz

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  1. Saba Hadidi
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Correspondence to Saba Hadidi.

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Hadidi, S., Shiri, F. & Norouzibazaz, M. A computational study on phenibut lactamization mechanism and the pH effects on the process. Theor Chem Acc 139, 100 (2020). https://doi.org/10.1007/s00214-020-02617-9

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