Vibrational Spectra of (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione (Perospirone): An Antipsychotic Agent

INTRODUCTION

(3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione (Perospirone) is mainly used for the treatment of schizophrenia and acute cases of bipolar mania. (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione ( Perospirone ) is a serotonin 5-HT2 receptor inverse agonist and dopamine D2 receptor antagonist based on receptor binding experiments that binds to both receptors with high affinity. (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione ( Perospirone ) is also a partial agonist at 5-HT1A receptors which are autoreceptors that stimulate the uptake of 5-HT and inhibit 5-HT release. It also interacts with D4 receptors and α₁- adrenergic receptors as an antagonist, as well as histamine H1 receptor an inverse agonist. Binding to these receptors may explain sedative and hypotensive actions. (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione ( Perospirone ) binds to D1 receptors with low affinity and minimal clinical significance. Antagonism at D2 receptors is believed to relieve the positive symptoms of schizophrenia such as delusions, hallucinations, and thought disorders. (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione ( Perospirone ) targets the mesolimbic patway to reverse the overactivity of the dopaminergic signalling via D2 receptors. 5-HT2A antagonism is thought to allevaite the negative symptoms and cognitive impairments of

play a role in dopamine release regulation. (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione ( Perospirone ) targets these receptors in the nigrostriatal pathway to reduce dopamine release and function. In contrast, 5-HT2A receptor antagonism may improve the negative symptoms by enhancing dopamine and glutamate release in the mesocortical pathway. 5-HT1A receptor activation further inhibits the release of 5-HT into the synaptic cleft. Plasma protein binding ratio is 92% with extensive binding to serum albumin and α1-acid glycoprotein. (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione ( Perospirone ) undergoes rapid and extensive first-pass metabolism in the liver; the metabolic pathways involve hydroxylation, N-dealkylation, and S-oxidation, which are catalyzed by CYP1A1, 2C8, 2D6, and 3A4. CYP3A4 is reported to have highest level of contribution in perospirone metabolism. Hydroxyperospirone is formed from hydroxylation of the the cyclohexane-1,2-dicarboximide moiety and retains pharmacological action by mediating antiserotonergic effects, although with lower affinity. (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione ( Perospirone ) using Gauss view program packages at the Becke3-Lee-Yang-Parr (B3LYP) level with standard 6-31G basis set.DFT computational codes are used in practise to investigate the structural, magnetic and electronic properties of molecules, materials and defects. DFT calculations allow the prediction and calculation of material behaviour on the basis of quantum mechanical considerations, without requiring higher order parameters such as fundamental material properties. DFT computational methods are applied for the study of systems to synthesis and processing parameters. In such systems, experimental studies are often encumbered by inconsistent results and non-equilibrium conditions. Examples of contemporary DFT applications include studying the effects of dopants on phase transformation behaviour in oxides, magnetic behaviour in dilute magnetic semiconductor materials.

DFT is supported by many quantum chemistry and solid state physics software packages, often along with other methods Optimized geometrical structure of (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione( Perospirone );

Fig 1 The vibrational frequencies of the solid phase FT-IR and FT-Raman spectra of (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione (Perospirone) were recorded in the regions 3500-500 and 3500-100 cm(-1), respectively. The optimized geometry, frequency and intensity of the vibrational bands of (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione (Perospirone) were obtained by the Restricted Hartree-Fock (RHF) density functional theory (DFT) with complete relaxation in the potential energy surface using 6-31G basis set. The harmonic vibrational frequencies for (3aR, 7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione ( Perospirone ) were calculated and the scaled values have been compared with experimental values of FTIR and FT-Raman spectra. The observed and the calculated frequencies are found to be in good agreement. The harmonic vibrational wave numbers and intensities of vibrational bands of (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione (Perospirone) with its cation and anion were calculated and compared with the neutral Thiothixene. The DFT calculated HOMO and LUMO energies shows that charge transfer occurs within the molecule. DFT calculations allow the prediction and calculation of material behavior on the basis of quantum mechanical considerations, without requiring higher order parameters such as fundamental material properties.

Infrared and Raman spectra of different crystalline forms of the same organic compound can be used to identify a pure crystal form and quantify a mixture of two forms. Many organic compounds have one or more crystalline or polymorphic forms. The observed differences in the spectra of different polymorphs include changes in frequencies, relative intensities, band contours and the number of bands.The IR and Raman spectra of (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione ( Perospirone ) an antipsychotics compound have been computed optimized geometrical structure of pharmaceutical compound (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione ( Perospirone ) were also evaluate from the calculation of intensities. Then the following figures show the calculated IR and Raman spectra of Optimized geometrical structure (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione ( Perospirone ).These calculations were done by using B3LYP/6˗31G methods.

Dipole moment, the measure of the electrical polarity of a system of chargesThe electric dipole moment is a measure of the separation of positive and negative electrical charges within a system, that is, a measure of the system's overall polarity.Bond dipole moment of Optimized geometrical structural compound is the measurement of polarity of a chemical bond and also known as the mathematical product of the separation of the ends of a dipole and the magnitude of the charges. The dipole moment creates by unequal sharing of electron in optimized geometrical molecules by their atoms. Dipole moment and energy of the medically active compound (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione ( Perospirone ) is shown in following table:- 27.211eV = 2625kJ/mol = 627.5kcal/mol.)

The most important orbitals in a molecule are the frontier molecular orbitals, called highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO).These orbitals determine the way the molecule interacts with other species. The frontier orbital gap helps characterize the chemical reactivity and kinetic stability of the molecule. A molecule with a small frontier orbital gap is more polarizable and is generally associated with a high chemical reactivity, low kinetic stability and is also termed as soft molecule. HOMO and LUMO are types of molecular orbitals. The acronyms stand for "highest occupied molecular orbital" and "lowest unoccupied molecular orbital", respectively. The energy difference between the HOMO and LUMO is termed the HOMO–LUMOgap. HOMO and LUMO are sometimes called frontier orbitalsin frontier molecular orbital theory. The difference in energy between these two frontier orbitals can be used to predict the strength and stability of transition metal complexes, as well as the colors they produce in solution. Energy levels of the frontier molecular orbital‘s especially HOMO, LUMO as well as their spatial distributions are important parameters for determining the optoelectronic properties. The density plot of the HOMO and LUMO of (3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione ( Perospirone ) is calculated at B3LYP/6-31G level of theory and are shown in Figure;

The energy gap between HOMO and LUMO has been used to prove the bioactivity from intermolecular charge transfer. The energy gap measures the kinetic stability of the molecules. The HOMO and LUMO energy gap show the charge transfer interaction taking place within the molecule. The HOMO and LUMO energy calculated by B3LYP /6-31G method as shown below in table:-

In molecular geometry, bond length or bond distance is the average distance between nuclei of two bonded atoms in a molecule. It is a transferable property of a bond between atoms of fixed types, relatively independent of the rest of the molecule. Molecular geometries can be specified in terms of bondlengths, bond angles and torsional angles. The bond length is defined to be the average distance between the nuclei of two atoms bonded together in any given molecule. A bond angleis the angle formed between three atoms across at least two bonds. The such as bond lengths, bond angle are the optimized structural parameters , so these parameters were determined at B3LYP level theory with 6-31G basis set and they are presented in a table, which is given below –

C45-C42 1.56536 H49-C48 1.07000 H55-C54 1.07000 C55-C51 1.56031 O4-C1 1.25841 C1-N5 1.49067 C56-C2 1.52953 C2-O3 1.25840 N5-C6 1.47000 H7-C6 1.07001 C6-C9 1.54002 C9-C12 1.53995

N30-C19 1.47001 C22-N31 1.47001 N31-C26 1.46993 N32-S33 1.72836 C26-C27 1.55612 C36-C38 1.54922 C40-C34 1.54541 C29-S33 1.74069

H41-C40-C34 120.038 S33-C29-C34 129.445 H39-C38-C40 119.870 H37-C36-C27 120.898 N32-S33-C29 94.374 N31-C26-N32 110.109 H23-C19-C22 120.652 N30-C18-C20 118.879 C15-N30-C18 109.996 H13-C12-H14 109.472 H11-C9-C6 109.474 C2-N5-C6 109.226 O3-C2-N5 125.787 O4-C1-C54 124.263 C56-C54-H55 115.496 H52-C51-H53 77.124 C42-C45-C48 109.546 H47-C45-H46 109.642

(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione (Perospirone) is on progress. It will be reported very soon.

I would like to thank my parents, who push for me to have good education. They made me enjoy learning new things and take new heights in life. We are very grateful to the DSMNR University Lucknow for the facility provided.

1. Chattopadhyay A, ed. (2007). Serotonin receptors in neurobiology. Boca Raton: CRC Press. ISBN 0-8493-3977-4. Archived from the original on 31 December 2015. 2. Gross G, Geyer MA (2012). Current Antipsychotics. Springer. pp. 88–89. doi:10.1007/978-3-642-25761-2. ISBN 978-3-642-25761-2. Archived from the original on 2013-10-13. 3. Sanchez M (May 2012). Farmacología y endocrinologíadelcomportamiento. Editorial UOC. pp. 148–149. ISBN 978-84-9788-424-2. Archived from the original on 25 November 2017. 4. "Archived copy". Archived from the original on 11 October 2016. Retrieved 27 September 2017. 5. "Archived copy". Archived from the original on 18 August 2017. Retrieved 7 May 2017. 6. Csernansky JG (6 December 2012). Antipsychotics. Springer Science & Business Media. pp. 360–. ISBN 978-3-642-61007-3. 7. William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia. Elsevier. pp. 1077–. ISBN 978-0-8155-1856-3. 8. William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia. Elsevier. pp. 1102–. ISBN 978-0-8155-1856-3. 9. Protiva, M. (2010). "ChemInform Abstract: Fifty Years in Chemical Drug Research". ChemInform. 23 (9): no–no. doi:10.1002/chin.199209338. ISSN 0931-7597. 11. Isbister GK, Balit CR, Macleod D, Duffull SB (August 2010). "Amisulpride overdose is frequently associated with QT prolongation and torsades de pointes". Journal of Clinical Psychopharmacology. 30 (4): 391–5. doi:10.1097/JCP.0b013e3181e5c14c. PMID 20531221. 12. Deeks ED, Keating GM (January 2010). "Blonanserin: a review of its use in the management of schizophrenia". CNS Drugs. 24 (1): 65–84. doi:10.2165/11202620-000000000-00000. PMID 20030420. 13. José Miguel Vela; Helmut Buschmann; JörgHolenz; Antonio Párraga; Antoni Torrens (2007). Antidepressants, Antipsychotics, Anxiolytics: From Chemistry and Pharmacology to Clinical Application. Weinheim: Wiley-VCH. p. 520. ISBN 3-527-31058-4. 14. Roth, BL; Driscol, J. "PDSP Ki Database" (HTML). Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017. 15. Silvestre JS, Prous J (2005). "Research on adverse drug events. I. Muscarinic M3 receptor binding affinity could predict the risk of antipsychotics to induce type 2 diabetes". Methods Find ExpClinPharmacol. 27 (5): 289–304. doi:10.1358/mf.2005.27.5.908643. PMID 16082416. 16. Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL (2003). "H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs". Neuropsychopharmacology. 28 (3): 519–26. doi:10.1038/sj.npp.1300027. PMID 12629531. 17. Burstein ES, Ma J, Wong S, Gao Y, Pham E, Knapp AE, Nash NR, Olsson R, Davis RE, Hacksell U, Weiner DM, Brann MR (2005). "Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist". J. Pharmacol. Exp. Ther. 315 (3): 1278–87.

18. William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia. Elsevier. pp. 3214–. ISBN 978-0-8155-1856-3. 19. Edward Shorter (2009). Before Prozac: The Troubled History of Mood Disorders in Psychiatry. Oxford University Press, USA. pp. 51–. ISBN 978-0-19-536874-1 20. Chakrabarti A, Bagnall A, Chue P, Fenton M, Palaniswamy V, Wong W, Xia J (October 2007). Chakrabarti A, ed. "Loxapine for schizophrenia" (PDF). The Cochrane Database of Systematic Reviews (4): on 7 December 2013. 21. Harvey PD, Ogasa M, Cucchiaro J, Loebel A, Keefe RS (April 2011). "Performance and interview-based assessments of cognitive change in a randomized, double-blind comparison of lurasidone vs. ziprasidone". Schizophrenia Research. 127 (1–3): 188–94. doi:10.1016/j.schres.2011.01.004. PMID 21277745. 22. Röhricht F, Gadhia S, Alam R, Willis M (2012). "Auditing clinical outcomes after introducing off-licence prescribing of atypical antipsychotic melperone for patients with treatment refractory schizophrenia". TheScientificWorldJournal. 2012: 512047. doi:10.1100/2012/512047. 23. Molindone Hydrochloride. Martindale: The Complete Drug Reference. The Royal Pharmaceutical Society of Great Britain. 30 January 2013. Retrieved 5 November 2013. 24. Leucht S, Helfer B, Hartung B (January 2014). "Perazine for schizophrenia". The Cochrane Database of Systemati Reviews(1): CD002832. DOI:10.1002/14651858.CD002832.pub3. PMID 24425538. 25. Onrust SV, McClellan K (April 2001). "Perospirone" (PDF). CNS Drugs. 15 (4): 329–37; discussion 338. doi:10.2165/00023210-200115040-00006. PMID 11463136. Archived from the original (PDF) on 4 November 2013. 26. Wu S, Xing Q, Gao R, Li X, Gu N, Feng G, He L: Response to chlorpromazine treatment may be associated with polymorphisms of the DRD2 gene in Chinese schizophrenic patients. NeurosciLett. 2005 Mar 7;376(1):1-4. Epub 2004 Dec 2. extrapyramidal syndrome in Chinese schizophrenic patients. ActaPharmacol Sin. 2006 Aug;27(8):966-70. 28. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. 29. Seeman P: Dopamine D2 receptors as treatment targets in schizophrenia. ClinSchizophrRelat Psychoses. 2010 Apr;4(1):56-73. doi: 10.3371/CSRP.4.1.5. 30. Brayfield A, ed. (23 September 2011). Perospirone. Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 3 November 2013. 31. Hartung B, Sampson S, Leucht S (March 2015). "Perphenazine for schizophrenia". The Cochrane Database of Systematic Reviews(3): CD003443. doi:10.1002/14651858.CD003443.pub3. PMID 25749632. 32. Mothi M, Sampson S (November 2013). "Pimozide for schizophrenia or related psychoses". The Cochrane Database of Systematic Reviews (11): CD001949. DOI:10.1002/14651858.CD001949.pub3. PMID 24194433. 33. Wang J, Sampson S (April 2014). "Sulpiride versus placebo for schizophrenia". The Cochrane Database of Systematic Reviews(4): CD007811. DOI:10.1002/14651858.CD007811.pub2. PMID 24729184. 34. Fenton M, Rathbone J, Reilly J, Sultana A (July 2007). Reilly J, ed. "Thioridazine for schizophrenia" (PDF). The Cochrane Database of Systematic Reviews (3): CD001944. doi:10.1002/14651858.CD001944.pub2. PMID 17636691. Archived from the original on 3 September 2015. 35. Marques LO, Lima MS, Soares BG (2004). Marques Ld, ed. "Trifluoperazine for schizophrenia" (PDF). The Cochrane Database of Systematic Reviews (1): CD003545. DOI:10.1002/14651858.CD003545.pub2. PMID 14974020. Archived from the original on 7 December 2013. generation antipsychotic. Int J ClinPract 2009; 63: pp. 1237-48. 37. Food and Drug Administration. FDA approves Fanapt to treat schizophrenia. www.fda.gov/NewsEvents/newsroom/ Press Announcements/ APRIL 2012 DELHI PSYCHIATRY JOURNAL Vol. 15 No.1 Delhi Psychiatry Journal 2012; 15:(1) © Delhi Psychiatric Society 207 ucm149578 (accessed 2010 Nov 3). 38. Kalkman HO, Subramanian N, Hoyer D. Extended radioligand binding profile of iloperidone: a broad spectrum dopamine/ serotonin/norepinephrine receptor antagonist for the management of psychotic disorders. Neuropsychopharmacology. 2001; 25 : 904-14. 39. Nnadi CU, Malhotra AK. Clinical and pharmacogenetic studies of iloperidone. Per Med 2008; 5: pp. 367-75. 40. Yasui-Furukori N, Furukori H, Nakagami T, Saito M, Inoue Y, Kaneko S, Tateishi T: Steady-state pharmacokinetics of a new antipsychotic agent perospirone and its active metabolite, and its relationship with prolactin response. Ther Drug Monit. 2004 Aug;26(4): pp. 361-5 41. Onrust SV, McClellan K: Perospirone. CNS Drugs. 2001;15(4): pp. 329-37; discussion 338. 42. Kishi T, Iwata N: Efficacy and tolerability of perospirone in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. CNS Drugs. 2013 Sep; 27(9): pp. 731-41. DOI: 10.1007/s40263-013-0085-7. 43. Takeuchi T, Furuta K, Hirasawa T, Masaki H, Yukizane T, Atsuta H, Nishikawa T: Perospirone in the treatment of patients with delirium. Psychiatry ClinNeurosci. 2007 Feb;61(1): pp. 67-70. 44. Zou JJ, Liu L, Di B, Ding L, Zhu YB, Fan HW, Xiao DW, Wang GJ: Estimation of Perospirone in Human Plasma by LC–MS–MS and Its Application to Pharmacokinetics Study Chromatographia. 2008 August 1;68(3-4): pp. 239–243. 45. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 553-563). Edinburgh: Elsevier/Churchill Livingstone.

Micromolecular and Biophysics laboratory, Department Of physics, Dr. Shakuntala Mishra National and Rehabilitation University, Mohan Road, Lucknow