Medicinal Chemistry Research

, Volume 25, Issue 12, pp 2752–2772 | Cite as

Anti-nociceptive effect of some synthesized smaller chain tripeptides and tetrapeptides in mice

  • Kandasamy Nagarajan
  • Vinay Kumar
  • Parul Grover
  • Roma Ghai
  • Pritesh Kumar Rai
  • Shamshir Alam
  • Umakant Bajaj
Original Research


The present study describes an approach to synthesize the smaller chain tripeptides and tetrapeptides and to test their antinociceptive potency in mice. Based on rational drug design using hydrophobic ratio and total net charge as descriptors, five leads were selected, viz., Met-Arg-Tyr (MRY), Met-Val-Tyr (MVY), Met-Ile-Cys-Tyr (MICY), Met-Trp-Lys-Tyr (MWKY) and Phe-Trp-Lys-Tyr (FWKY) from the subjected 65 templates and synthesized by dicyclohexyl carbodiimide coupling using polystyrene as solid support. All the synthesized compounds were purified by column chromatography and further confirmed by melting point, infrared, proton nuclear magnetic resonance and mass spectral datas. Acute toxicity studies were performed for dose selection in all the compounds using OECD guidelines 423 (Annexure 2b). Antinociceptive potency of peptides was tested in Swiss albino mice using acetic acid writhing and hot plate method. The LD50 cut-off mg/kg body weight for tripeptides (MRY, MVY) and tetrapeptides (Met-Ile-Cys-Tyr, Met-Trp-Lys-Tyr, Phe-Trp-Lys-Tyr) were found to be 500–2000 mg/kg and 200–300 mg/kg respectively. The tripeptide MVY have shown maximum antinociceptive action with an average number of writhing as 13 at 150 mg/kg body weight by writhing method, whereas the tripeptide Met-Arg-Tyr have shown maximum potency with the average reaction time of 5.75 min after 15 min at a dose of 150 mg/kg by hot plate method, which clearly indicated that the tripeptides are comparatively potent antinociceptive agents than the tetrapeptides for central neuropathic pain.


Tetrapeptides Tripeptides Acute toxicity Antinociceptive activity Drug design Met-Arg-Tyrosine 



The authors remain thankful to Dr. Umakant Bajaj, Principal, KIET School of Pharmacy for the provision of laboratory facilities.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. Argoff CE (2013) Topical analgesics in the management of acute and chronic pain. Mayo Clin Proc 88(2):195–205CrossRefPubMedGoogle Scholar
  2. Barua CC, Talukdar A, Begum SA, Lahon LC, Sarna DK, Pathak DC et al. (2010) Antinociceptive activity of methanolic extract of leaves of Achyranthus aspera Linn. (Amaranthaceae) in animal models of nociception. Indian J Exp Biol 48:817–821PubMedGoogle Scholar
  3. Bhargave CS (2013) Study of effect of nimesulide co-administered with calcium channel blockers on nociception, in Swiss albino mice. Int J Pharmacol Bio Sci 7(1):55–60Google Scholar
  4. Boman H (2003) Antibacterial peptides: basic facts and emerging concepts. J Intern Med 254:197–215CrossRefPubMedGoogle Scholar
  5. Bruehl S, Apkarian AV, Ballantyne JC, Berger A, Borsook D, Chen WG et al. (2013) Personalized medicine and opioid analgesic prescribing for chronic pain: opportunities and challenges. J Pain 14(2):103–113CrossRefPubMedPubMedCentralGoogle Scholar
  6. Cases RP, Aracil A, Merino JM, Gallar J, Paya EP, Belmonte C et al. (2000) Arginine rich peptides are blockers of VR-1 channels with analgesic activity. FEBS Letts 481(2):131–136CrossRefGoogle Scholar
  7. Committee on Advancing pain research, and Education; Institute of Medicine (2011) Relieving pain in America: a blueprint for transforming prevention, care, education, and research. National Academic Press, WashingtonGoogle Scholar
  8. Gao B, Li H, Xia D, Sun S, Ba X (2011) Amphiphilic dendritic peptides: synthesis and behavior as an organogelator and liquid crystal. Beilstein J Org Chem 7:198–203CrossRefPubMedPubMedCentralGoogle Scholar
  9. Garabedian BS, Dardenne M, Pleau JM, Saade NE (2002) Potent analgesic and anti-inflammatory actions of a novel thymulin related peptide in the rat. Br J Pharmacol 136(6):947–955CrossRefGoogle Scholar
  10. Gross JH (2010) Mass spectrometry-a textbook. Springer International, Heidelberg, 300–307Google Scholar
  11. Kiso Y, Kitagawa K, Nobuyuki K, Akita T, Takagi H, Amano H et al. (2010) Neo-kyotorphin (Thr-Ser-Lys-Tyr-Arg), a new analgesic peptide. FEBS Letts 155(2):281–284CrossRefGoogle Scholar
  12. Koeter HBMW (1990) The science and the art of regulatory toxicology: how to deal with alternative tests. OECD Environment Monographs, USAGoogle Scholar
  13. Mogil JS (2009) Animal models of pain: progress and challenges. Nat Rev Neurosci 10:283–294CrossRefPubMedGoogle Scholar
  14. Ogawa T, Miyamae T, Murayama K, Okuyama K, Okayama T, Hagiwara M et al. (2002) Synthesis and structure activity relationships of an orally available and long acting analgesic peptide, Nα-Amidino-Tyr-D-Arg-Phe-Me β Ala-OH (ADAMB). J Med Chem 45(23):5081–5089CrossRefPubMedGoogle Scholar
  15. Pawar SD, Gaidhani SN, Anandan T, Lavekar GS, Kumari S, Padhi MM et al. (2011) Evaluation of anti-inflammatory, analgesic and anti-arthritic activity of yograja guggulu in laboratory animals. Int J Pharmacol Bio Sci 5(2):17–25Google Scholar
  16. Poole S, Bristow AF, Lorenzetti BB, Gaines Das RE, Smith TW, Ferreira SH (1992) Peripheral analgesic activities of peptides related to α-melanocyte stimulating hormone and interleukin-1β. Br J Pharmacol 106(2):489–492CrossRefPubMedPubMedCentralGoogle Scholar
  17. Silbert BS, Lipkowski AW, Cepeda MS, Szyfelbein SK, Osgood PF, Carr DB (1991) Analgesic activity of a novel bivalent opioid peptide compared to morphine via different routes of administration. Agents Actions 33(3-4):382–387CrossRefPubMedGoogle Scholar
  18. Silverstein RM, Webster FX (2005) Spectrometric identification of organic compounds. Wiley India (P) Ltd., New DelhiGoogle Scholar
  19. Stahl E (1969) Thin layer chromatography. Springer International, BerlinCrossRefGoogle Scholar
  20. Tegge W, Bonafe CFS, Teichmann A, Erck C (2010) Synthesis of peptides from α- and β-tubulin containing glutamic acid side chain linked oligo-glu with defined length. Int J Peptides. doi:  10.1155/2010/189396
  21. Terasaki T, Deguchi Y, Sato H, Hirai K, Tsuji A (1991) Invivo transport of a dynorphin-like analgesic peptide, E-2078, through the blood brain barrier: an application of brain microdialysis. Pharmaceutical Res 8(7):815–820CrossRefGoogle Scholar
  22. Waltraud B, Halina M, Shaaban M, Thomas S, Pierre RJM, Jean-Louis J et al. (2001) Analgesic and anti-inflammatory effects of two novel (kappa)-opioid peptides. Anesthesiology 94(6):1034–1044CrossRefGoogle Scholar
  23. Wilcox NL (1994) Regulatory aspects in the US Food and drug administration: in alternative methods in toxicology. Mary Ann-Liebert Inc., USAGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Kandasamy Nagarajan
    • 1
  • Vinay Kumar
    • 2
  • Parul Grover
    • 1
  • Roma Ghai
    • 2
  • Pritesh Kumar Rai
    • 1
  • Shamshir Alam
    • 3
  • Umakant Bajaj
    • 4
  1. 1.Department of Pharmaceutical ChemistryKIET School of PharmacyGhaziabadIndia
  2. 2.Department of PharmacologyKIET School of PharmacyGhaziabadIndia
  3. 3.Department of Clinical PharmacyUnaizah College of Pharmacy, Qassim UniversityBuraydahKingdom of Saudi Arabia
  4. 4.KIET School of PharmacyGhaziabadIndia

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