New Arylpiperazine Derivatives as Antagonists of the Human Cloned 5-HT 4 Receptor Isoforms

Archive ouverte

Curtet, Sophie | Soulier, Jean-Louis | Zahradnik, Ivan | Giner, Mireille | Berque-Bestel, Isabelle | Mialet, Jeanne | Lezoualc'H, Frank | Donzeau-Gouge, Patrick | Sicsic, Sames | Fischmeister, Rodolphe | Langlois, Michel

Edité par CCSD ; American Chemical Society -

International audience. New derivatives of arylpiperazine 9 were designed from ML 10302, a potent 5-HT 4 receptor agonist in the gastrointestinal system. Compounds were synthesized by condensation of a number of available arylpiperazines or heteroarylpiperazines with 2-bromoethyl 4-amino-5chloro-2-methoxybenzoate. They were evaluated in binding assays on the recently cloned human 5-HT 4(e) isoform stably expressed in C6 glial cells with [ 3 H]GR 113808 as the radioligand. The affinity values (K i) depended upon the substituent on the aromatic ring. A chlorine atom produced a marked drop in activity (K i > 100 nM), while a m-methoxy group gave a compound with nanomolar affinity (K i) 3 nM). The most potent compounds were the heterocyclic derivatives with pyrimidine, pyrazine, pyridazine, or pyridine moieties (compounds 9r, 9t, 9u, 9x, respectively). K i values for 9a and 9r were determined for the 5-HT 4(a) , 5-HT 4(b) , 5-HT 4(c) , and 5-HT 4(d) receptor isoforms transiently expressed in COS cells. The results indicated that the compounds were not selective. They produced an inhibition of the 5-HT-stimulated cyclic AMP synthesis in the C6 glial cells stably expressing the 5-HT 4(e) receptor and shifted the 5-HT concentration-effect curve on adenylyl cyclase activity with pK D values of 7.44 and 8.47, respectively. In isolated human atrial myocytes, 9r antagonized the stimulatory effect of 5-HT on the L-type calcium current (I Ca) with a K D value of 0.7 nM.

• Description
• Sujet/Public
• Outil
• Outil d'anticipation
• Mémoire et thèse
• Gestion