Effects of EGIS-7625, a selective and competitive 5-HT2B receptor antagonist

Our aim was to specify the 5-HT(2) subtype selectivity of EGIS-7625 (1-benzyl-4-[(2-nitro-4-methyl-5-amino)-phenyl]-piperazine), a new 5-HT(2B) ligand, in receptor binding studies and characterize its pharmacology at 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors in in vivo experiments and in isolated or...

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Published in:Cardiovascular drugs and therapy 2003-09, Vol.17 (5-6), p.427-434
Main Authors: KOVACS, Aniko, GACSALYI, Istvan, TIHANYI, Kasoly, SPEDDING, Michael, SZENASI, Gabor, WELLMANN, Janos, SCHMIDT, Eva, SZÜCS, Zsuzsanna, DUBREUIL, Valérie, NICOLAS, Jean Paul, BOUTIN, Jean, BOZSING, Daniel, EGYED, Andras
Format: Article
Language:English
Subjects:
Animals
Binding, Competitive
Biological and medical sciences
Cardiovascular system
Eating - drug effects
Gastric Fundus - drug effects
Gastric Fundus - physiology
Humans
In Vitro Techniques
Male
Medical sciences
Miscellaneous
Motor Activity - drug effects
Muscle Contraction - drug effects
Muscle, Smooth - drug effects
Muscle, Smooth - physiology
Pharmacology. Drug treatments
Piperazines - pharmacology
Pulmonary Artery - drug effects
Pulmonary Artery - physiology
Rabbits
Rats
Rats, Wistar
Receptor, Serotonin, 5-HT2A - metabolism
Receptor, Serotonin, 5-HT2B - metabolism
Serotonin 5-HT2 Receptor Antagonists
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Summary:Our aim was to specify the 5-HT(2) subtype selectivity of EGIS-7625 (1-benzyl-4-[(2-nitro-4-methyl-5-amino)-phenyl]-piperazine), a new 5-HT(2B) ligand, in receptor binding studies and characterize its pharmacology at 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors in in vivo experiments and in isolated organs, in vitro. EGIS-7625 had high affinity for recombinant human 5-HT(2B) receptors (pK(i) = 9.0) but much weaker affinity for 5-HT(2A) and 5-HT(2C) receptors (pK(i) = 6.2 and 7.7, respectively). In the classic 5-HT(2B) 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 pA(2) of 9.4. On the other hand, EGIS-7625 was a weak competitive antagonist at 5-HT(2A) receptors as it shifted 5-HT-induced concentration-response curves to the right at high concentrations (pA(2) = 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-HT(2C) receptors, in vivo. In conclusion, EGIS-7625 is a potent, selective and competitive 5-HT(2B) antagonist that seems to be a good research tool for the separation of the functional roles of vascular 5-HT(2A) and 5-HT(2B) receptors.
ISSN:0920-3206
1573-7241
DOI:10.1023/B:CARD.0000015857.96371.43