Multivalent ligands for the serotonin 5-HT4 receptor

Federica Castriconi, Marco Paolino, Alessandro Donati, Germano Giuliani, Maurizio Anzini, Laura Mennuni, Chiara Sabatini, Marco Lanza, Gianfranco Caselli, Francesco Makovec, Maria Sbraccia, Paola Molinari, Tommaso Costa, Andrea Cappelli

Research output: Contribution to journalArticlepeer-review

Abstract

5-HT4 receptors are known to form constitutive dimers in membranes. To explore whether multivalency can enhance ligand interactions and/or efficacy in 5-HT4 receptors, the structure of the partial agonist ML10302 was modified with oligo(ethylene glycol) chains, thus generating, by a gradual approach, short and long tethered bivalent or tetravalent ligands and the corresponding spanner-linked monovalent controls. Both bivalent and tetravalent ligands displayed a 10-20-fold increase in binding affinity compared to appropriate controls, but no multivalent ligand showed greater binding energy than ML10302 itself. Furthermore, the direct assessment of receptor-Gs interaction and studies of cAMP signalling indicated that multivalency does not enhance the efficacy of ML10302.

Original languageEnglish
Pages (from-to)647-651
Number of pages5
JournalMedChemComm
Volume8
Issue number3
DOIs
Publication statusPublished - Jan 1 2017

ASJC Scopus subject areas

  • Biochemistry
  • Pharmaceutical Science

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