New Arylpiperazine Derivatives as Antagonists of the Human Cloned 5-HT4 Receptor Isoforms
| Autor: | Ivan Zahradnik, Mireille Giner, Michel Langlois, Sames Sicsic, Isabelle Berque-Bestel, Jeanne Mialet, Jean-Louis Soulier, Rodolphe Fischmeister, Frank Lezoualc'h, Sophie Curtet, Patrick Donzeau-Gouge |
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| Přispěvatelé: | Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Slovak Academy of Sciences (SAS), Cardiologie cellulaire et moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Privé Jacques Cartier [Massy], FISCHMEISTER, RODOLPHE |
| Rok vydání: | 2000 |
| Předmět: |
Patch-Clamp Techniques
Calcium Channels L-Type Pyrimidine Pyrazine Stereochemistry In Vitro Techniques Chemical synthesis Piperazines Cell Line Pyridazine Radioligand Assay chemistry.chemical_compound Drug Discovery para-Aminobenzoates Radioligand Animals Humans Protein Isoforms Cloning Molecular [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] Receptor [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] chemistry.chemical_classification COS cells Myocardium Aromatic amine musculoskeletal system chemistry Receptors Serotonin COS Cells Molecular Medicine Receptors Serotonin 5-HT4 Serotonin Antagonists 4-Aminobenzoic Acid Neuroglia Adenylyl Cyclases |
| Zdroj: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, 2000, 43 (20), pp.3761-3769. ⟨10.1021/jm0009538⟩ |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm0009538 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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