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 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.
Kovács
Anikó
A
Division of Preclinical Research, EGIS Pharmaceuticals Ltd., Budapest, Hungary.
Gacsályi
Istvan
I
Wellmann
János
J
Schmidt
Eva
E
Szücs
Zsuzsanna
Z
Dubreuil
Valérie
V
Nicolas
Jean Paul
JP
Boutin
Jean
J
Bózsing
Daniel
D
Egyed
Andras
A
Tihanyi
Kasoly
K
Spedding
Michael
M
Szénási
Gábor
G
D000818:Animals; D001667:Binding, Competitive; D004435:Eating / Q000187:drug effects; D005748:Gastric Fundus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists
C489704:EGIS7625; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists