Design and synthesis of specific probes for human 5-HT4 receptor dimerization studies.
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.
Soulier
Jean-Louis
JL
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.
Russo
Olivier
O
Giner
Mireille
M
Rivail
Lucie
L
Berthouze
Magali
M
Ongeri
Sandrine
S
Maigret
Bernard
B
Fischmeister
Rodolphe
R
Lezoualc'h
Frank
F
Sicsic
Sames
S
Berque-Bestel
Isabelle
I
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
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