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Kyotorphin analogues containing unnatural amino acids: synthesis, analgesic activity and computer modeling of their interactions with μ-receptor

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Abstract

Kyotorphin (KTP; Tyr-Arg) an endogenous neuropeptide is potently analgesic when delivered directly to CNS. An effort to enhance the potency, enzymatic stability and improving bioavailability of KTP is the modification with unnatural amino acids. The aims of presented study were: (1) To synthesize new analogues of kyotorphin containing unnatural amino acids: norcanavaine (NCav) and norcanaline (NCan), structural analogues of arginine and ornithine, respectively; (2) To understand the influence of the arginine mimetics on the pharmacological properties of KTP analogues, through examination their effects on the paw pressure nociceptive threshold; (3) To find relationship between the structure and obtained biological effects of the all synthesized kyotorhin analogues, by molecular docking with μ-opioid receptor. As a result of our work four new kyotorphin analogues containing NCan and NCav were obtained. A correlation between the data from the in vivo test and docking results was found. This allows a better elucidation of the ligand-receptor interactions, the prediction of biological activity of the newly synthesized compounds, and to generate compounds with increased biological effects.

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Abbreviations

KTP:

Kyotorphin

CNS:

Central nervous system

MOR:

μ-Opioid receptors

PP:

Paw-pressure nociceptive test

Cav:

Canavanine

NCav:

Norcanavanine

Can:

Canaline

NCan:

Norcanaline

NsArg:

Norsulfoarginine

Piv-Cl:

Pivaloyl chloride

DIPEA:

N,N-diisopropylethylamine

Boc:

Di-tert-butyl dicarbonate

Z:

Carboxybenzyl

References

  • Aleksiev B, Stoev S (1971) Substitution of sulfur-containing amino carbonic acids, peptides and protein corpuscles with chlorine. 6. Synthesis of substituted 2-amino-2-carboxyethanolsulfonamides. Pharmazie 26:469–473

    CAS  PubMed  Google Scholar 

  • Befort K, Tabbara L, Bausch S, Chavkin C, Evans C, Kieffer B (1996) The conserved aspartate residue in the third putative transmembrane domain of the delta-opioid receptor is not the anionic counterpart for cationic opiate binding but is a constituent of the receptor binding site. Mol Pharmacol 49:216–223

    CAS  PubMed  Google Scholar 

  • Bocheva A, Pajpanova T, Golovinsky E, Lazarova-Bakarova M (1996) Studies on pain modulation by newly-synthesized analogues of kyotorphin. In: Monduzzi Editore S.p.A Menagement of Pain a World Perspective II, Bologna, Italy, pp 15–18

  • Bocheva A, Dzambazova-Maximova E, Dzimbova T, Pajpanova T, Golovonsky (2006) Analgesic action of norsulphoarginine kyotorphin analogues. Compt Rend Acad bul Sci 59:219–222

    CAS  Google Scholar 

  • Brakadanska T, Pajpanova T, Bocheva A, Petkov VV, Golovinsky E (2001) Effects of some non-proteinogenic on nociception. Bulg Chem Comm 33:79–82

    CAS  Google Scholar 

  • Börjesson U, Hünenberger PH (2001) Explicit-solvent molecular dynamics simulation at constant pH: methodology and application to small amines. J Chem Phys 114:9706–9719

    Article  Google Scholar 

  • Chen P, Bodor N, Wu WM, Prokai L (1998) Strategies to target kyotorphin analogues to the brain. J Med Chem 41:3773–3781

    Article  CAS  PubMed  Google Scholar 

  • Dzambazova EB, Landzhov BV, Bocheva AI, Bozhilova-Pastirova AA (2011) Effects of D-kyotorphin on nociception and NADPH-d neurons in rat’s periaqueductal gray after immobilization stress. Amino Acids 41:937–944

    Article  CAS  PubMed  Google Scholar 

  • Dzambazova-Maximova E, Bocheva A, Todorov S (2003) Analgesic action of kyotorphin and its canavanine analogues in rats. Role of histamine- and nitric oxide-ergic systems. Comp rend Acad bul Sci 56:75–80

    CAS  Google Scholar 

  • Dzimbova T, Pajpanova T, Golovinsky E (2003) Synthesis of some sulfoguanidino group-containing amino acids. Collect Czech Chem C 6:12–14

    CAS  Google Scholar 

  • Dzimbova T, Pajpanova T, Golovinsky E (2006) Synthesis of novel kyotorphins containing non-proteinogenic amino acid norsulfoarginine. Bulg Chem Commun 38:45–48

    CAS  Google Scholar 

  • Dzimbova T, Pajpanova T, Tabacova S, Golovinsky E (2007) Oxyamino- and sulfoguanidino containing amino acids. Synthesis and antibacterial activity. In: Cordopatis P (ed) 5th Hellenic Forum on Bioactive Peptides, TYPORAMA, Greece, pp 223–227

  • Dzimbova T, Miladinova E, Mohr S, Detcheva R, Balacheva A, Schmid MG, Pajpanova T (2011) Sulfo- and oxy-analogues of arginine: synthesis, analysis and preliminary biological screening. Croat Chem Acta 84:447–453

    Article  CAS  Google Scholar 

  • Garthwaite J (1991) Glutamate, nitric oxide and cell–cell signaling in the nervous system. Trends Neurosci 14:60–67

    Article  CAS  PubMed  Google Scholar 

  • George SR, Fan T, Xie ZD, Tse R, Tam V, Varghese G, O’Dowd BF (2000) Oligomerization of μ- and δ-opioid receptors: generation of novel functional properties. J Biol Chem 275:26128–26135

    Article  CAS  PubMed  Google Scholar 

  • Hansen DW, Stapelfeld A, Savage MA, Reichman M, Hammond DL, Haaseth RC, Mosberg HI (1992) Systemic analgesic activity and.delta.-opioid selectivity in [2,6-dimethyl-Tyr1, D-Pen2, D-Pen5]encephalin. J Med Chem 35:684–687

    Article  CAS  PubMed  Google Scholar 

  • Harima A, Shimizu H, Takagi H (1991) Analgesic effect of l-arginine in patients with persistent pain. Eur Neuropsychopharmacol 1:529–533

    Article  CAS  PubMed  Google Scholar 

  • Jones G, Wilett P, Glen RC, Leach AR, Taylor R (1997) Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267:727–748

    Article  CAS  PubMed  Google Scholar 

  • Kawabata A, Umedo N, Takadi H (1993) Arginine exerts a dual role in nociceptive processing in the brain: involvement of the kyotorphin met-enkephalin pathway and NO-cyclic GMP pathway. Br J Pharmacol 109:73–79

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kawabata K, Iwatsubo K, Takaya S, Takagi H (1996) Central antinociceptive effect of l-ornithine, a metabolite of l-arginine, in rats and mice. Eur J Pharmacol 256:23–31

    Article  Google Scholar 

  • Kolaeva SG, Semenova TP, Santalova IM, Moshkov DA, Anoshkina IA, Golozubova V (2000) Effects of l-thyrosyl-l-arginine (kyotorphin) on the behavior of rats and goldfish. Peptides 21:1331–1336

    Article  CAS  PubMed  Google Scholar 

  • Machuqueiro M, Baptista AM (2007) The pH-dependent conformational states of kyotorphin: a constant-ph molecular dynamics study. Biophys J 92:1836–1845

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pajpanova T, Bocheva A, Stoev S, Kasakov L, Golovinsky E (1992) Synthesis and biological properties of peptide tyrosine-canavanine a structural analogue of kyotorphin. Compt Rend Acad Bul Sci 45:45–48

    CAS  Google Scholar 

  • Pajpanova T, Stoev S, Golovinsky E, Krauss G-J, Miersch J (1997) Canavanine derivatives useful in peptide synthesis. Amino Acids 12:191–204

    Article  CAS  Google Scholar 

  • Peterlin-Mašič L, Kikelj D (2001) Arginine mimetics. Tetrahedron 57:7073–7105

    Article  Google Scholar 

  • Randall LO, Selitto JJ (1957) A method for measurement of analgesic activity on inflamed tissue. Arch Int Pharmacol 79:409–419

    Google Scholar 

  • Riordan JF, McElvany KD, Borders CL Jr (1977) Arginyl residues: anion recognition sites in enzymes. Science 195:884–886

    Article  CAS  PubMed  Google Scholar 

  • Shiomi H, Ueda H, Takagi H (1981) Isolation and identification of an analgesic opioid dipeptide kyotorphin (TYR-ARG) from bovine brain. Neuropharmacology 20:633–638

    Article  CAS  PubMed  Google Scholar 

  • Stanchev M, Pajpanova T, Golovinsky E (2000) Synthesis and antibacterial activity of some new non-proteinogenic amino acids containing thiazole residues. Amino Acids 18:177–191

    Article  CAS  PubMed  Google Scholar 

  • Takagi H, Shiomi H, Ueda H, Amano H (1979) A novel analgesic dipeptide from bovine brain is a possible Met-enkephalin releaser. Nature 282:410–412

    Article  CAS  PubMed  Google Scholar 

  • Ueda H, Inoue M (2000) In vivo signal transduction of nociceptive response by kyotorphin (tyrosine-arginine) through gαi- and inositol trisphosphate-mediated Ca2+ influx. Mol Pharmacol 57:108–115

    CAS  PubMed  Google Scholar 

  • Ueda H, Tatsumi K, Shiomi H, Takagi H (1982) Analgesic dipeptide, kyotorphin (Tyr-Arg), is highly concentrated in the synaptosomal fraction of the rat brain. Brain Res 231:222–224

    Article  CAS  PubMed  Google Scholar 

  • Ueda H, Ming G, Hazato T, Katayama T, Takagi H (1985) Degradation of kyotoprhin by a purified membrane-bound-aminopeptidase from monkey brain: potentiation of kyotorphin-induced analgesia by a highly effective inhibitor, bestatin. Life Sci 36:1865–1871

    Article  CAS  PubMed  Google Scholar 

  • Ueda H, Matsumoto S, Yoshihara Y, Fukushima N, Takagi H (1986a) Uptake and release of kyotorphin in rat brain synaptosomes. Life Sci 38:2405–2411

    Article  CAS  PubMed  Google Scholar 

  • Ueda H, Yoshihara Y, Takagi H (1986b) A putative met-enkephalin releaser, kyotorphin enhances intracellular Ca2+ in the synaptosomes. Biochem Biophys Res Commun 137:897–902

    Article  CAS  PubMed  Google Scholar 

  • Ueda H, Yoshihara Y, Fukushima N, Shiomi H, Nakamura A, Takagi H (1987) Kyotorphin (tyrosine-arginine) synthetase in rat brain synaptosomes. J Biol Chem 262:8165–8173

    PubMed  Google Scholar 

  • Ueda H, Inoue M, Weltrowska G, Schiller PW (2000) An enzymatically stable kyotorphin analog induces pain in subattomol doses. Peptides 21:717–722

    Article  CAS  PubMed  Google Scholar 

  • Videnov G, Aleksiev B, Stoev M, Paipanova T, Jung G (1993) Tmob side chain-protected s-cysteine- and homo-s-cysteinesulfonamides, their Nα-protected and Nω-aminoethylated derivatives. Liebigs Ann Chem. doi:10.1002/jlac.1993199301150

    Google Scholar 

  • Zakutskii AN, Chalisova NI, Subbotina TF (2008) Functional arginine-containing amino acid sequences in peptides and proteins. Russ J Bioorg Chem 34:135–144

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work has been supported by Grant MY-FS-13 and DVU 01/197 of the National Science Fund of the Ministry of Education and Science of Republic of Bulgaria and COST Action CM0801 Project DO 02-135/31.07.2009.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Block 21, 1113, Sofia, Bulgaria

    Tatyana Dzimbova & Tamara Pajpanova

  2. Department of Pathophysiology, Faculty of Medicine, Medical University of Sofia, 2, Zdrave Str, 1431, Sofia, Bulgaria

    Adriana Bocheva

Authors
  1. Tatyana Dzimbova
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  2. Adriana Bocheva
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  3. Tamara Pajpanova
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Correspondence to Tatyana Dzimbova.

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Dzimbova, T., Bocheva, A. & Pajpanova, T. Kyotorphin analogues containing unnatural amino acids: synthesis, analgesic activity and computer modeling of their interactions with μ-receptor. Med Chem Res 23, 3694–3704 (2014). https://doi.org/10.1007/s00044-014-0953-9

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