Cardiovascular Drugs and Therapy

, Volume 17, Issue 5–6, pp 427–434

Effects of EGIS-7625, a Selective and Competitive 5-HT2B Receptor Antagonist

  • Anikó Kovács
  • Istvan Gacsályi
  • János Wellmann
  • Éva Schmidt
  • Zsuzsanna Szücs
  • Valérie Dubreuil
  • Jean Paul Nicolas
  • Jean Boutin
  • Daniel Bózsing
  • Andras Egyed
  • Kasoly Tihanyi
  • Michael Spedding
  • Gábor Szénási
Article

Abstract

Our aim was to specify the 5-HT2 subtype selectivity of EGIS-7625 (1-benzyl-4-[(2-nitro-4-methyl-5-amino)-phenyl]-piperazine), a new 5-HT2B ligand, in receptor binding studies and characterize its pharmacology at 5-HT2A, 5-HT2B and 5-HT2C receptors in in vivo experiments and in isolated organs, in vitro. EGIS-7625 had high affinity for recombinant human 5-HT2B receptors (pKi = 9.0) but much weaker affinity for 5-HT2A and 5-HT2C receptors (pKi = 6.2 and 7.7, respectively). In the classic 5-HT2B test, EGIS-7625 produced a concentration-related parallel rightward shift in the concentration-response relationship for the 5-HT-induced smooth muscle constriction in rat stomach fundus strips with a pA2 of 9.4. On the other hand, EGIS-7625 was a weak competitive antagonist at 5-HT2A receptors as it shifted 5-HT-induced concentration-response curves to the right at high concentrations (pA2 = 6.7) in rabbit pulmonary artery strips. The m-chlorophenylpiperazine-induced hypomotility and hypophagia was only partially attenuated by EGIS-7625 even at a dose of 30 mg/kg i.p. while mianserin, a non-selective 5-HT antagonist was almost fully effective in these tests at 3 mg/kg i.p., suggesting weak antagonistic effect of EGIS-7625 at neuronal 5-HT2C receptors, in vivo. In conclusion, EGIS-7625 is a potent, selective and competitive 5-HT2B antagonist that seems to be a good research tool for the separation of the functional roles of vascular 5-HT2A and 5-HT2B receptors.

serotonin rat stomach fundus rabbit pulmonary artery recombinant human 5-HT2 receptors 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Hoyer D, Clarke DE, Fozard JR, et al. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 1994; 46: 157-203.Google Scholar
  2. 2.
    Bonhaus DW, Flippin LA, Greenhouse RJ, et al. RS-127445: Aselective, high affinity, orally bioavailable 5-HT2B receptor Antagonist. Br J Pharmacol 1999; 127: 1075-1082.Google Scholar
  3. 3.
    Fitzgerald LW, Burn TC, Brown BS, et al. Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol 2000; 57: 75-81.Google Scholar
  4. 4.
    Knowles ID, Ramage AG. Evidence for a role for central 5-HT2B as well as 5-HT2A receptors in cardiovascular regulation in anaesthetized rats. Br J Pharmacol 1999; 128: 530-542.Google Scholar
  5. 5.
    Knowles ID, Ramage AG. Evidence that activation of central 5-HT(2B) receptors causes renal sympathoexcitation in anaesthetized rats. Br J Pharmacol 2000; 129: 177-183.Google Scholar
  6. 6.
    Kennett GA, Ainsworth K, Trail B, Blackburn TP. BW 723C86, a 5-HT2B receptor agonist, causes hyperphagia and reduced grooming in rats. Neuropharmacology 1997; 36: 233-239.Google Scholar
  7. 7.
    Kennett GA, Trail B, Bright F. Anxiolytic-like actions ofBW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated. Neuropharmacology 1998; 37: 1603-1610.Google Scholar
  8. 8.
    Meneses A. 5-HT system and cognition. Neurosci Biobehav Rev 1999; 23: 1111-1125.Google Scholar
  9. 9.
    Clineschmidt BV, Reiss DR, Pettibone DJ, Robinson JL. Characterisation of 5-hydroxytryptamine receptors in rat stomach fundus. J Pharmacol Exp Ther 1985; 235: 696-708.Google Scholar
  10. 10.
    Ellis ES, Byrne C, Murphy OE, Tilford NS, Baxter GS. Mediation by 5-hydroxytryptamine2B receptors of endotheliumdependent relaxation in rat jugular vein. Br J Pharmacol 1995; 114: 400-404.Google Scholar
  11. 11.
    Watts SW, Harris B. Is functional upregulation of the 5-HT2B receptor in deoxycorticosterone acetate salt-treated rats blood pressure dependent? Gen Pharmacol 1999; 33: 439-447.Google Scholar
  12. 12.
    Watts SW, Fink GD. 5-HT2B receptor antagonist LY-272015 is antihypertensive in DOCA-salt-hypertensive rats. Am J Physiol 1999; 276: H944-952.Google Scholar
  13. 13.
    Baxter GS. Novel discriminatory ligands for 5-HT2B receptors. !Behav Brain Res 1996; 73: 149-152.Google Scholar
  14. 14.
    Cohen M, Audia J, Nelson D. 5-HT2B receptors: The road to therapeutic application. ID Drug Alert 1997; 2: 1-5.Google Scholar
  15. 15.
    Kovács A, Schmidt É, Tihanyi K, Egyed A, Szénási G. Pharmacological effects of EGIS-7625, a new and selective 5-HT2B blocker. Fund Clin Pharmacol 1999; 13(Suppl. 1): 281s, PT86.Google Scholar
  16. 16.
    Leysen JE, Niemegeers CJE, Van Nueten JM, Laduron PM. [3H]Ketanserin (R 41 468), a Selective 3H-Ligand for Serotonin2 receptor Binding Sites. Mol Pharmacol 1981; 21: 301-314.Google Scholar
  17. 17.
    Peroutka SJ. Pharmacological differentiation and characterization of 5-HT1A, 5-HT1B, and 5-HT1C binding sites in rat frontal cortex. J Neurochem 1986; 47: 529-540.Google Scholar
  18. 18.
    Pazos A, Hoyer D, Palacios JM. The binding of serotonergic ligands to the porcine choroid plexus: Characterization of a new type of serotonin recognition site. Eur J Pharmacol 1985; 106: 539-546.Google Scholar
  19. 19.
    Baxter GS, Murphy OE, Blackburn TP. Further characterization of 5-hydroxytryptamine receptors (putative 5-HT2B) in rat stomach fundus longitudinal muscle. Br J Pharmacol 1994; 112: 323-331.Google Scholar
  20. 20.
    Prinssen EP, Koek W, Kleven MS. The effects of antipsychotics with 5-HT2C receptor affinity in behavioral assays selective for 5-HT2C receptor antagonist properties of compound. Eur J Pharmacol 2000; 388: 57-67.Google Scholar
  21. 21.
    Arunlakshana O, Schild HO. Some quantitative uses of drug antagonists. Br J Pharmacol 1959; 14: 48-58.Google Scholar
  22. 22.
    Van Rossum JM. Cumulative dose-response curves. II.Technique for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch Int Pharmacodyn 1963; 143: 99-330.Google Scholar
  23. 23.
    Bonhaus DW, Bach C, De Souza A, et al. The pharmacology and distribution of human 5-hydroxytryptamine2B (5-HT2B) receptor gene products: Comparison with 5-HT2A and 5-HT2C receptors. Br J Pharmacol 1995; 115: 622-628.Google Scholar
  24. 24.
    Glusa E, Pertz HH. Further evidence that 5-HT-induced relaxation of pig pulmonary artery is mediated by endothelial 5-HT2B receptors. Br J Pharmacol 2000; 130: 692-698.Google Scholar
  25. 25.
    Bonhaus DW, Weinhardt KK, Taylor M, et al. RS-102221: A novel high affinity and selective, 5-HT2C receptor antagonist. Neuropharmacology 1997; 36: 621-629.Google Scholar
  26. 26.
    Martin JR, Bos M, Jenck F, et al. 5-HT2C receptor agonists: Pharmacological characteristics and therapeutic potential. J Pharmacol Exp Ther 1998; 286: 913-924.Google Scholar
  27. 27.
    Wainscott DB, Lucaites VL, Kursar JD, Baez M, Nelson DL. Pharmacologic Characterization of the Human 5-Hydroxytryptamine2B Receptor: Evidence for Species Differences. J Pharmacol Exp Ther 1996; 276: 720-727.Google Scholar
  28. 28.
    Choi DS, Kellermann O, Richard S, et al. Mouse 5-HT2B receptor-mediated serotonin trophic functions. Ann NY Acad Sci 1998; 861: 67-73.Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Anikó Kovács
    • 1
  • Istvan Gacsályi
    • 1
  • János Wellmann
    • 1
  • Éva Schmidt
    • 1
  • Zsuzsanna Szücs
    • 1
  • Valérie Dubreuil
    • 2
  • Jean Paul Nicolas
    • 2
  • Jean Boutin
    • 2
  • Daniel Bózsing
    • 1
  • Andras Egyed
    • 1
  • Kasoly Tihanyi
    • 1
  • Michael Spedding
    • 2
  • Gábor Szénási
    • 1
  1. 1.Division of Preclinical Research, EGIS Pharmaceuticals LtdFrance
  2. 2.Institut de Recherches Internationales Servier, Croissy sur SeineFrance

Personalised recommendations