Pharmaceutical Chemistry Journal

, Volume 44, Issue 4, pp 167–170 | Cite as

Molecular-biological problems of drug design and mechanism of drug action

Experimental investigation of the biological stability of the dipeptide neuroleptic dilept
  • N. V. Mesonzhnik
  • S. S. Boiko
  • S. A. Appolonova
  • G. M. Rodchenkov
  • V. P. Zherdev

Major metabolites of the new original peptide (neurotensin analog) dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester), which was designed at the Zakusov Institute of Pharmacology, were isolated and identified using an HPLC—MS/MS method. The structures of the metabolites were confirmed using reference compounds obtained by retro synthesis. The stability of dilept in vitro in human and rat plasma and in vivo upon peroral administration in rats was studied. It is established that dilept is rapidly hydrolyzed in rat plasma to N-caproyl-L-prolyl-L-tyrosine (metabolite M1) whereas it is more stable in human plasma in vitro. In experiments with peroral administration of dilept in rats, metabolite M2 (N-caproyl-L-proline) was found besides M1 in the blood stream. It is suggested that M2 is a product of the enzymatic hydrolysis of dilept by peptidases.

Key words

dilept dipeptide neuroleptic HPLC—MS metabolism 


  1. 1.
    T.A. Gudasheva, N. I. Zaitseva, N. A. Bondarenko, et al., Khim.-farm. Zh., 31(11), 10 – 16 (1997).Google Scholar
  2. 2.
    T. A. Gudasheva, T. A .Voronina, R. U. Ostrovskaya, et al., J. Med. Chem., 41, 284 – 290 (1998).CrossRefPubMedGoogle Scholar
  3. 3.
    S. B. Seredenin, T. A. Boronina, T. A. Gudasheva, et al., RF Pat. No. 2091390 (1995).Google Scholar
  4. 4.
    M. V. Retyunskaya, L. S. Guzevatykh, N. A. Bondarenko, et al., Byull. Eksp. Biol. Med., 136, No. 11, 527 – 523 (2003).Google Scholar
  5. 5.
    R. U. Ostrovskaya, M. V. Retyunskaya, L. S. Guzevatykh, et al., Eksp. Klin. Farmakol., 68(1),3–6 (2005).Google Scholar
  6. 6.
    M. Boules, E. Richelson, and P. Fredrickson, Peptides, 27, 2523 – 2533 (2006).CrossRefPubMedGoogle Scholar
  7. 7.
    N. V. Arkhipenko, S. A. Appolonova, T. G. Sobolevskii, et al., Khim.-farm. Zh., 43(5), 53 – 56 (2009).Google Scholar
  8. 8.
    L. Hu, Meeting Report Prodrugs, June 28-29, USA (2004).Google Scholar
  9. 9.
    K. Zhang, B. Hee, C. Lee, et al., Drug Metabol. Disposition, 29(5), 729 – 734 (2001).Google Scholar
  10. 10.
    Neotame. Joint Expert Committee of Food Additives (JECFA), 52 (2004).Google Scholar
  11. 11.
    J. D. Cleary and J. W. Taylor, Drug Intell. Clin. Pharm., 20(3), 177 – 186 (1986).PubMedGoogle Scholar
  12. 12.
    S. Meisel, A. Shamiss, and T.Rosenthal, Clin. Pharmacokinet., 26(1),7–15 (1994).CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2010

Authors and Affiliations

  • N. V. Mesonzhnik
    • 1
    • 2
  • S. S. Boiko
    • 1
  • S. A. Appolonova
    • 2
  • G. M. Rodchenkov
    • 2
  • V. P. Zherdev
    • 1
  1. 1.Zakusov Institute of PharmacologyRussian Academy of Medical SciencesMoscowRussia
  2. 2.Moscow Antidoping CenterMoscowRussia

Personalised recommendations