Advertisement

Medicinal Chemistry Research

, Volume 21, Issue 4, pp 477–486 | Cite as

Synthesis, 5-HT1A and 5-HT2A receptor affinity and QSAR study of 1-benzhydryl-piperazine derivatives with xanthine moiety at N4

  • Iva Valkova
  • Alexander Zlatkov
  • Krystyna Nędza
  • Irini Doytchinova
Original Research

Abstract

Three novel 1-benzhydryl-piperazines with xanthine moiety at N4 were synthesized and tested for 5-HT1A and 5-HT2A receptor affinity. One of the compounds showed the highest affinity (58.6 nM) and selectivity (34 times) to 5-HT2A receptor known for this class of compounds. A set of the three new and 31 previously synthesized 1-arylpiperazines with xanthine moiety at N4 was compiled and a QSAR study was performed in order to rationalize the further synthesis. It was found that the 5-HT1A affinity depends on the shape of the molecules (ovality and number of circuits), the distribution of the electron density in the structures (partial charges at piperazine N1 and xanthine N1) and their charge transfer ability (HOMO energy). The 5-HT2A affinity depends on the lipophilicity of the ligands and the distribution of the electron density in the structures (partial charges at piperazine N4 and xanthine O6). The QSAR results are in a good agreement with known pharmacophore models.

Graphical Abstract

Keywords

Piperazine Xanthine 5-HT1A and 5-HT2A QSAR 

Notes

Acknowledgments

This work was supported by grant from the Medical Science Council of the Medical University of Sofia (project 5-I/2009).

References

  1. Bodor N, Gabanyi Z, Wong C-K (1989) A new method for the estimation of partition coefficient. J Am Chem Soc 111:3783–3786CrossRefGoogle Scholar
  2. Bojarski AJ (2006) Pharmacophore models for metabotropic 5-HT receptor ligands. Curr Topics Med Chem 6:2005–2026CrossRefGoogle Scholar
  3. Bojarski AJ, Cegła MT, Charakchieva-Minol S, Mokrosz MJ, Mackowiak M, Mokrosz JL (1993) Structure-activity relationship studies of CNS agents. Part 9. 5-HT1A and 5-HT2 receptor affinity of some 2- and 3-substituted 1,2,3,4-tetrahydro-β-carbolines. Pharmazie 48:289–294PubMedGoogle Scholar
  4. Cheng Y, Prusoff WH (1973) Relationship between the inhibition constant ([K.sub.i]) and the concentration of inhibitor which causes 50 per cent inhibition ([I.sub.50]) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108PubMedCrossRefGoogle Scholar
  5. Chlon G, Pawlowski M, Duszynska B, Szaro A, Tatarczynska E, Klodzinska A, Chojnacka-Wojcik E (2001) Synthesis, 5-HT1A and 5-HT2A receptor activity of new 1-phenylpiperazinylpropyl derivatives with arylalkyl substituents in position 7 of purine-2, 6-dione. Pol J Pharmacol 53:359–368PubMedGoogle Scholar
  6. Chojnacka-Wojcik E, Klodzinska A, Drabczynska A, Pawlowski M, Charakchieva-Minol S, Chlon G, Gorczyca M (1995) A new putative 5-HT1A receptor antagonist of the 1-arylpiperazine class of ligands. Eur J Med Chem 30:587–592CrossRefGoogle Scholar
  7. Daly JW (2007) Caffeine analogs: biomedical impact. Cell Mol Life Sci 64:2153–2169PubMedCrossRefGoogle Scholar
  8. Dewar MJS, Zoebisch EG, Healy EF, Stewart JJP (1985) AM1: A new general purpose quantum mechanical model. J Am Chem Soc 107:3902–3909CrossRefGoogle Scholar
  9. Gagausov J, Peikov P, Davkov D, Sharankov K (1987) Synthesis of 8-brom-methylxanthines. Farmacia (Sofia) 37:8–10Google Scholar
  10. Glennon RA, Westkaemper RB, Bartyzel P (1991) Medicinal chemistry of serotonergic agents. In: Peroutka SJ (ed) Serotonin receptor subtypes: basic and clinical aspects. Wiley-Liss, New York, pp 19–64Google Scholar
  11. Hocquet A, Langgard M (1998) An evaluation of the MM + force field. J Mol Model 4:94–112CrossRefGoogle Scholar
  12. Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP (1994) International union of pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 46:157–203PubMedGoogle Scholar
  13. Kang S, Green JP (1970) Correlation between activity and electronic state of hallucinogenic amphetamines. Nature 226:645PubMedCrossRefGoogle Scholar
  14. Kolaczkowski M, Zajdel P, Fhod O, Duszynska B, Tatarczynska E, Pawlowski M (2005) Synthesis and 5-HT1A/5-HT2A activity of some butyl analogs in the group of phenylpiperazine alkyl pyrimido[2,1-f]theophyllines. Pharmacol Reports 57:229–235Google Scholar
  15. Kolb VM (1987) Electron-transfer and charge-transfer clastic binding hypotheses for drug-receptor interactions. Pharm Res 4:450–456PubMedCrossRefGoogle Scholar
  16. Leardi R, Boggia R, Terrile M (1992) Genetic algorithms as a strategy for feature selection. J Chemometrics 6:267–281CrossRefGoogle Scholar
  17. Lopez-Rodriguez ML, Ayala D, Benhamu B, Morcillo MJ, Viso A (2002) Arylpiperazine derivatives acting at 5-HT1A receptors. Curr Med Chem 9:443–469PubMedGoogle Scholar
  18. Mokrosz JL, Strekowski L, Duszynska B, Harden DB, Mokrosz MJ, Bojarski AJ (1994) Structure-activity relationship studies of CNS agents. Part 14. Structural requirements for the 5-HT1A and 5-HT2 receptor selectivity of simple 1-(2-pyrimidinyl)piperazine derivatives. Pharmazie 49:801–806PubMedGoogle Scholar
  19. Nagamoto T, Rashid M, Muntasir HA, Komiyama T (2004) Functions of 5-HT2A receptor and its antagonists in the cardiovascular system. Pharmacol Therap 104:59–81CrossRefGoogle Scholar
  20. Nichols DE, Nichols CD (2008) Serotonin receptors. Chem Rev 108:1614–1641PubMedCrossRefGoogle Scholar
  21. Oh SJ, Ha HJ, Chi DY, Lee HK (2001) Serotonin receptor and transporter ligands—current status. Curr Med Chem 8:999–1034PubMedGoogle Scholar
  22. Ouagazzal A-M, Grottick AJ, Moreau J-L, Higgins GA (2001) Pharmacological analysis and comparison between two rat strains. Neuropsychopharmacol 25:565–575CrossRefGoogle Scholar
  23. Pawlowski M, Katlabi J, Drabczynska A, Duszynska B, Charakchieva-Minol S, Deren-Wesolek A, Tatarczynska E, Chojnacka-Wojcik E, Mokrosz MJ, Bojarski AJ (1999) New 9- or 10-arylpiperazinoalkyl substituted pyrimido- or diazepino[2, 1-f]purines with partial or full 5-HT1A agonistic activity. Eur J Med Chem 34:167–175CrossRefGoogle Scholar
  24. Pawlowski M, Chlon G, Obniska J, Zejc A, Charakchieva-Minol S, Mokrosz MJ (2000) Synthesis, 5-HT1A and 5-HT2A receptor affinity of new 1-phenylpiperazinylpropyl derivatives of purine-2, 6-and pyrrolidine-2, 5-diones. Il Farmaco 55:461–468PubMedCrossRefGoogle Scholar
  25. Peikov P, Sidzhakova D, Gagausov J (1988) Methods of synthesis of pentoxiphylline. Farmacia (Sofia) 38:1–4Google Scholar
  26. Peikov P, Zlatkov Al, Gagausov J, Kalinkova G (1990) Preparation of some 8-(bromoalkylamino)-caffeines and infrared studies. Farmacia (Sofia) 49:1–6Google Scholar
  27. Roth BL (1994) Multiple serotonin receptors: clinical and experimental aspects. Ann Clin Psychiatry 6:67–78PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Iva Valkova
    • 1
  • Alexander Zlatkov
    • 1
  • Krystyna Nędza
    • 2
  • Irini Doytchinova
    • 1
  1. 1.Faculty of PharmacyMedical University of SofiaSofiaBulgaria
  2. 2.Institute of PharmacologyPolish Academy of SciencesKrakówPoland

Personalised recommendations