, Volume 17, Issue 5-6, pp 427-434

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.