title: Design and synthesis of specific probes for human 5-HT4 receptor dimerization studies.
abstract: Recently, human 5-HT4 receptors have been demonstrated to form constitutive dimers in living cells. To evaluate the role of dimerization on the 5-HT4 receptor function, we investigated the conception and the synthesis of bivalent molecules able to influence the dimerization process. Their conception is based on a model of the 5-HT4 receptor dimer derived from protein/protein docking experiments. These bivalent ligands are constituted by two ML10302 units, a specific 5-HT4 ligand, linked through a spacer of different sizes and natures. These synthesized bivalent ligands were evaluated in binding assays and cyclic AMP production on the 5-HT4(e/g) receptor isoform stably transfected in C6 glial cells. Our data showed that bivalent ligands conserved a similar affinity compared to the basal ML10302 unit. Nevertheless, according to the nature and the size of the spacer, the pharmacological profile of ML10302 is more or less conserved. In view of the interest of bivalent ligands for investigating the GPCR dimerization process, these 5-HT4 specific bivalent ligands constitute valuable pharmacological tools for the study of 5-HT4 receptor dimerization.
authors.affiliation: UMR C8076 (CNRS), Laboratoire de Reconnaissance Moléculaire et Synthèses, Faculté de Pharmacie, Université de Paris XI, Biocis, 5, rue Jean-Baptiste Clément, 92296 Châtenay-Malabry 92296, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Soulier
authors.forename: Olivier
authors.initials: O
authors.lastname: Russo
authors.forename: Mireille
authors.initials: M
authors.lastname: Giner
authors.forename: Lucie
authors.initials: L
authors.lastname: Rivail
authors.forename: Magali
authors.initials: M
authors.lastname: Berthouze
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ongeri
authors.forename: Bernard
authors.initials: B
authors.lastname: Maigret
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Fischmeister
authors.forename: Frank
authors.initials: F
authors.lastname: Lezoualc'h
authors.forename: Sames
authors.initials: S
authors.lastname: Sicsic
authors.forename: Isabelle
authors.initials: I
authors.lastname: Berque-Bestel
mesh_terms: D000249:Adenosine Monophosphate / Q000096:biosynthesis; D062365:Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D019281:Dimerization; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D044422:Receptors, Serotonin, 5-HT4 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D062366:para-Aminobenzoates
chemical_list: C117947:2-piperidinoethyl 4-amino-5-chloro-2-methoxybenzoate; D062365:Aminobenzoates; D008024:Ligands; D010880:Piperidines; D020033:Protein Isoforms; D062366:para-Aminobenzoates; D044422:Receptors, Serotonin, 5-HT4; D000249:Adenosine Monophosphate