Acta Scientific Pharmaceutical Sciences

Research ArticleVolume 1 Issue 2

Electrostatic Potential-Mapped Electron Density Surface and Conformation Analysis of an Antidepressant, Mirtazapine

IE Otuokere*

Department of Chemistry, Michael Okpara University of Agriculture, Umudike, Nigeria

*Corresponding Author: IE Otuokere, Department of Chemistry, Michael Okpara University of Agriculture, Umudike, Nigeria.

Received: May 31, 2017; Published: July 01, 2017

Citation: IE Otuokere. “Electrostatic Potential-Mapped Electron Density Surface and Conformation Analysis of an Antidepressant, Mirtazapine”. Acta Scientific Pharmaceutical Sciences 1.2 (2017).

Abstract

Mirtazapine (methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1]pyrido [2,3][2]benzazepine) is a medication with noradrenergic and specific serotonergic activity. Electrostatic potential-mapped electron density surface and conformation analysis of mirtazapine was carried out using ArgusLab 4.0.1 software. Electrostatic potential-mapped electron density surface showed the areas of the molecule that would be susceptible to nucleophilic and electrophilic attack. The geometry convergence curve predicted the minimum energy of the molecule. The predicted geometry energy was -90.575172 au (-56836.830000 kcal/mol). At this potential energy, mirtazapine will be able to interact effectively with the receptor.

Keywords: Mirtazapine; Arguslab; Conformation Analysis; Electrostatic Potential; Receptor

Abbreviations

  ESP: Electrostatic Potential

Introduction

  Mirtazapine (methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1] pyrido[2,3][2]benzazepine) is a medication with noradrenergic and specific serotonergic activity [1]. It inhibits the α2 adrenergic auto- and heteroreceptors (enhancing 5-hydroxytryptamine release), and by selection antagonizes the 5-HT2 5-hydroxytryptamine receptors within the central and peripheral systema nervosum. It additionally enhances 5-hydroxytryptamine neurotransmission at the 5-HT1 receptor and blocks the histaminergic (H1) and muscarinic receptors. This antidepressant is not a 5-hydroxytryptamine or catecholamine uptake substance however it has the ability to increase 5-hydroxytryptamine and catecholamine by alternative mechanisms of action [2]. Mirtazapine was introduced by Organon International in the United States in 1996 [3] as a noradrenergic and specific serotonergic medication (NaSSA). It is employed primarily for treatment of depression, major depressive disorder and other mood disorders [4,5]. It can also act as a medicament for anxiolytic, hypnotic and appetency stimulant. Structurally, it is the 6-aza analogue of mianserin [6] and can be classified as a tetracyclic medication (TeCA). The comparison of the efficacy and tolerability of 12 second-generation antidepressants was studied in 2009 [6]. It was discovered that mirtazapine was superior to other selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) [6].

  However, it has additionally been found helpful in assuaging generalized anxiety disorder [7,8], low appetite/underweight [9-11], nausea and vomiting [12-14], social anxiety disorder [15,16], obsessive-compulsive disorder [15,17], and post-traumatic stress disorder [15]. Mirtazapine and its derivatives might cause a discontinuance syndrome when the medication is stopped abruptly [18,19]. A gradual and slow reduction in dose is usually recommended to reduce discontinuance symptoms [20]. Effects of abrupt stoppage of treatment with mirtazapine might embody depression, anxiety, panic attacks, vertigo, restlessness, irritability, reduced appetency, insomnia, diarrhea, nausea, vomiting, flu-like symptoms like allergies and itching, headaches and typically hypomania or mania [20]. The structure of mirtazapine is shown in Figure 1.

  In conformation analysis, energy is decreased so as to induce rock bottom energy. The conformation with rock bottom energy is the most stable. In nature, low energy level is favourable. Understanding the electrostatic potential-mapped density surface and conformation of a molecule is important because it permits us to predict the reactivity of the molecule. The aim of conformation analysis is to work out atomic orientations that are the most stable. ArgusLab [21] is a molecular modelling graphics and drug style program for windows package. It is a software package for conformation analysis, single purpose energy calculations, electronic spectrum predictions, molecular orbital surfaces and molecular docking.

Figure 1:
 Structure of mirtazapine

Figure 1: Structure of mirtazapine

  We hereby present electrostatic potential-mapped electron density surface and conformation analysis of an antidepressant, mirtazapine.

Materials and Methods

  Geometry optimization study was performed on a window primarily based computer using ArgusLab and ACD laboratory ChemSketch software package. The chemical structure of mirtazapine was generated by ArgusLab. Diminution was performed with Parameterized Model three (PM3) semi-empirical using ArgusLab 4.0.1 software. The minimum potential energy was calculated by geometry convergence operation in ArgusLab software package. Electrostatic potential mapped on negatron density surface of mirtazapine was created. The minimum potential energy was calculated for drug receptor interaction through the geometry convergence map.

Results and Discussion

  The electrostatic potential-mapped electron density surface and geometry convergence curve of mirtazapine are shown in Figures 2 and 3 respectively. Final geometry optimized coordinates, geometry optimized bond length and geometry optimized bond angles of mirtazapine are presented in Tables 1 - 3 respectively.

Figure 2: 
Electrostatic potential-mapped electron density
surface of mirtazapine.

Figure 2: Electrostatic potential-mapped electron density surface of mirtazapine.

Figure 3: 
Geometry convergence curve of mirtazapine.

Figure 3: Geometry convergence curve of mirtazapine.

Atom X Y Z
C 16.549701 10.132548 0.003997
C 16.961337 8.708667 0.124094
C 17.487689 11.285460 0.141336
N 18.143823 8.174487 0.527106
C 18.937676 11.200564 0.119797
C 19.819033 10.056703 0.075609
C 19.474461 8.625286 0.174592
C 15.231331 10.402526 0.025517
C 14.713674 11.781813 0.056375
C 17.006128 12.536591 0.195900
C 15.561094 12.803683 0.153275
C 21.077653 10.368091 0.402055
C 22.109495 9.329014 0.536827
N 20.428527 7.721903 0.058697
C 21.784353 8.059266 0.308131
C 15.975604 7.740665 0.654381
N 16.060883 6.349686 0.299243
C 18.048771 6.854942 1.126927
C 16.991907 5.929555 0.712034
C 15.109748 5.416241 0.836185

Table 1: Final geometry optimized coordinates of mirtazapine.

Atoms Bond Length (Å)
1 2 (C)-(C) 1.458000
1 8 (C)-(C) 1.323387
1 3 (C)-(C) 1.458000
2 16 (C)-(C) 1.458000
2 4 (C)-(N) 1.433804
3 5 (C)-(C) 1.458000
3 10 (C)-(C) 1.323387
4 7 (N)-(C) 1.433804
4 18 (N)-(C) 1.433804
5 6 (C)-(C) 1.458000
6 12 (C)-(C) 1.323387
6 7 (C)-(C) 1.458000
7 14 (C)-(N) 1.301961
8 9 (C)-(C) 1.458000
9 11 (C)-(C) 1.323387
10 11 (C)-(C) 1.458000
12 13 (C)-(C) 1.458000
13 15 (C)-(C) 1.323387
14 15 (N)-(C) 1.433804
16 17 (C)-(N) 1.433804
17 19 (N)-(C) 1.433804
17 20 (N)-(C) 1.436817
18 19 (C)-(C) 1.458000

Table 2: Geometry optimized bond length of Mirtazapine.

Atoms Bond angles (o) Alternate bond angle (o)
2 1 8 (C)-(C)-(C) 120.000000 216.488007
2 1 3 (C)-(C)-(C) 120.000000 188.442082
1 2 16 (C)-(C)-(C) 120.000000 188.442082
1 2 4 (C)-(C)-(N) 120.000000 257.053574
8 1 3 (C)-(C)-(C) 120.000000 216.488007
1 8 9 (C)-(C)-(C) 120.000000 216.488007
1 3 5 (C)-(C)-(C) 120.000000 188.442082
1 3 10 (C)-(C)-(C) 120.000000 216.488007
16 2 4 (C)-(C)-(N) 120.000000 257.053574
2 16 17 (C)-(C)-(N) 120.000000 257.053574
2 4 7 (C)-(N)-(C) 120.000000 198.144139
2 4 18 (C)-(N)-(C) 120.000000 198.144139
5 3 10 (C)-(C)-(C) 120.000000 216.488007
3 5 6 (C)-(C)-(C) 120.000000 188.442082
3 10 11 (C)-(C)-(C) 120.000000 216.488007
7 4 18 (C)-(N)-(C) 120.000000 198.144139
4 7 6 (N)-(C)-(C) 120.000000 257.053574
4 7 14 (N)-(C)-(N) 120.000000 402.764879
4 18 19 (N)-(C)-(C) 120.000000 257.053574
5 6 12 (C)-(C)-(C) 120.000000 216.488007
5 6 7 (C)-(C)-(C) 120.000000 188.442082
12 6 7 (C)-(C)-(C) 120.000000 216.488007
6 12 13 (C)-(C)-(C) 120.000000 216.488007
6 7 14 (C)-(C)-(N) 120.000000 294.480480
7 14 15 (C)-(N)-(C) 120.000000 227.506158
8 9 11 (C)-(C)-(C) 120.000000 216.488007
9 11 10 (C)-(C)-(C) 120.000000 216.488007
12 13 15 (C)-(C)-(C) 120.000000 216.488007
13 15 14 (C)-(C)-(N) 120.000000 295.980973
16 17 19 (C)-(N)-(C) 120.000000 198.144139
16 17 20 (C)-(N)-(C) 120.000000 197.520556
19 17 20 (C)-(N)-(C) 120.000000 197.520556
17 19 18 (N)-(C)-(C) 120.000000 257.053574

Table 3: Geometry optimized bond angles of mirtazapine.

  Mapped surface was generated using ArgusLab software. This is a surface where one property is superimposed onto a surface created by another property. The foremost well-liked example of this is often to map the electrostatic potential (ESP) onto a surface of the negatron density. In ESP-mapped density surface, the negatron density surface offers the form of the surface whereas the ESP offers the colours. The potential energy felt by a positive test charge at a selected purpose in area is known as electrostatic potential. A negative ESP, is often a vicinity of stability for test charge. Conversely, a positive ESP, is often a vicinity of relative instability for the positive test charge. Thus, the favorability of a molecule to nucleophilic or electrophilic attack can be seen using ESP-mapped density surface. This surface is helpful for qualitative interpretations of chemical reactivity. In a different way to think about ESP-mapped density a surface is that it shows where the frontier negatron density for the molecule is greatest (or least) relative to the nuclei. In the ESP-mapped density surface of mirtazapine (Figure 2), the colours show the ESP on the negatron density surface. The red colour on the surface shows region of high electron density. Nucleophilic attack is likely to occur at these regions. The white portion on the surface is the methyl group. Electrophillic attack will occur at this region.

  The geometry convergence curve of mirtazapine (Figure 2) shows a reduction in energy from. The lowest energy obtained was -90.575172 au (-56836.830000 kcal/mol). At this point, the drug will be stable. At this point the drug will be able to interact with the receptor. The geometry optimized coordinates, bond length and bond angles (Table 1- 3) will give a conformation with the lowest potential energy and most stable conformation. Previous studies [22, 23] have shown that Arguslab software is reliable for the prediction of ESP-mapped density surface and minimum energy of a molecule.

Conclusion

  Arguslab software is reliable for the prediction of ESPmapped density surface and minimum energy of a molecule. The most feasible conformation mirtazapine to interact with the receptor is -90.575172 au (-56836.830000 kcal/mol). The ESPmapped density surface was used in the prediction of molecular reactivity.

Acknowledgements

  We are grateful for the research grant from Abia State Government, Nigeria.

Conflict of Interest

  No conflict of interest

Bibliography

  1. “International brand names for mirtazapine”. Drugs.com.
  2. “How Does Mirtazapine Induce Weight Gain?” Medscape.
  3. “REMERON (mirtazapine) tablet, film coated [Organon Pharmaceuticals USA]”. DailyMed. Organon Pharmaceuticals USA (2012).
  4. Gorman JM. “Mirtazapine: clinical overview”. The Journal of Clinical Psychiatry 60.17 (1999): 9-13.
  5. Benjamin S and Doraiswamy PM. “Review of the use of mirtazapine in the treatment of depression”. Expert Opinion on Pharmacotherapy 12.10 (2011): 1623-1632.
  6. Cipriani A., et al. “Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments metaanalysis”. Lancet 373.9665 (2009): 746-758.
  7. Anttila SA and Leinonen EV. “A review of the pharmacological and clinical profile of mirtazapine”. CNS Drug Reviews 7.3 (2001): 249-264.
  8. Goodnick PJ., et al. “Mirtazapine in major depression with comorbid generalized anxiety disorder”. The Journal of Clinical Psychiatry 60.7 (1999): 446-448.
  9. Landowski J. “[Mirtazapine--an antidepressant]”. Psychiatria Polska 36.6 (2002): 125-130.
  10. Chinuck RS., et al. “Appetite stimulants in cystic fibrosis: a systematic review”. Journal of Human Nutrition and Dietetics 20.6 (2007): 526-537.
  11. Davis MP., et al. “Management of symptoms associated with advanced cancer: olanzapine and mirtazapine. A World Health Organization project”. Expert Review of Anticancer Therapy 2.4 (2002): 365-376.
  12. Nutt DJ. “Tolerability and safety aspects of mirtazapine”. Human Psychopharmacology 17.1 (2002): S37-S41.
  13. Li TC., et al. “Mirtazapine relieves post-electroconvulsive therapy headaches and nausea: a case series and review of the literature”. The Journal of ECT 27.2 (2011): 165-167.
  14. Kast RE and Foley KF. “Cancer chemotherapy and cachexia: mirtazapine and olanzapine are 5-HT3 antagonists with good antinausea effects”. European Journal of Cancer Care 16.4 (2007): 351-354.
  15. Croom KF., et al. “Mirtazapine: a review of its use in major depression and other psychiatric disorders”. CNS Drugs 23.5 (2009): 427-452.
  16. Muehlbacher M, et al. “Mirtazapine treatment of social phobia in women: a randomized, double-blind, placebo-controlled study”. Journal of Clinical Psychopharmacology 25.6 (2005): 580-583.
  17. Koran LM., et al. “Mirtazapine treatment of obsessive-compulsive disorder”. Journal of Clinical Psychopharmacology 21.5 (2001): 537-539.
  18. Möller HJ. “Is there evidence for negative effects of antidepressants on suicidality in depressive patients? A systematic review”. European Archives of Psychiatry and Clinical Neuroscience 256.8 (2006): 476-496.
  19. Abo-Zena RA., et al. “Hypertensive urgency induced by an interaction of mirtazapine and clonidine”. Pharmacotherapy 20.4 (2000): 476-478.
  20. Benazzi F. “Mirtazapine withdrawal symptoms”. Canadian Journal of Psychiatry 43.5 (1998): 525.
  21. Thompson MA, ArgusLab 4.0, Planaria Software LLC, Seattle, WA (2007).
  22. Otuokere IE., et al. “In Silico geometry optimization, excited state properties of (2E)-N-Hydroxy-3-[3-(Phenylsulfamoyl) phenyl]prop-2-enamide (Belinostat) and its molecular doching studies with Ebola Virus Glycoprotein”. Asian Journal of Pharmaceutical Sciences 5.3 (2015): 131-137.
  23. Otuokere IE., et al. “Conformational analysis of a potent anticancer drug, 3 - (4-amino-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione (lenalidomide)”. International Journal of Material Chemistry and Physics 1.3 (2015): 402-406.

Copyright: © 2017 IE Otuokere. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



News and Events


  • Submission Timeline for Regular Issue
    The last date for submission of articles for regular Issues is December 20, 2019.
  • Publication Certificate
    Authors will be issued a "Publication Certificate" as a mark of appreciation for publishing their work.
  • Best Article of the Issue
    The Editors will elect one Best Article after each issue release. The authors of this article will be provided with a certificate of “Best Article of the Issue”.
  • Welcoming Article Submission
    Acta Scientific delightfully welcomes active researchers for submission of articles towards the upcoming issue of respective journals.
  • Contact US