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

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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 (pK i = 9.0) but much weaker affinity for 5-HT2A and 5-HT2C receptors (pK i = 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.

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Authors and Affiliations

  1. Division of Preclinical Research, EGIS Pharmaceuticals Ltd, France

    Anikó Kovács, Istvan Gacsályi, János Wellmann, Éva Schmidt, Zsuzsanna Szücs, Daniel Bózsing, Andras Egyed, Kasoly Tihanyi & Gábor Szénási

  2. Institut de Recherches Internationales Servier, Croissy sur Seine, France

    Valérie Dubreuil, Jean Paul Nicolas, Jean Boutin & Michael Spedding

Authors
  1. Anikó Kovács
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  2. Istvan Gacsályi
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  3. János Wellmann
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  4. Éva Schmidt
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  5. Zsuzsanna Szücs
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  6. Valérie Dubreuil
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  7. Jean Paul Nicolas
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  8. Jean Boutin
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  9. Daniel Bózsing
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  10. Andras Egyed
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  11. Kasoly Tihanyi
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  12. Michael Spedding
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  13. Gábor Szénási
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Kovács, A., Gacsályi, I., Wellmann, J. et al. Effects of EGIS-7625, a Selective and Competitive 5-HT2B Receptor Antagonist. Cardiovasc Drugs Ther 17, 427–434 (2003). https://doi.org/10.1023/B:CARD.0000015857.96371.43

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  • DOI: https://doi.org/10.1023/B:CARD.0000015857.96371.43

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