Multivalent ligands for the serotonin 5-HT4 receptor

  • Medchemcomm. 2017 Feb 9;8(3):647-651. doi: 10.1039/c6md00458j.
Federica Castriconi  1 ,  Marco Paolino  1 ,  Alessandro Donati  1 ,  Germano Giuliani  1 ,  Maurizio Anzini  1 ,  Laura Mennuni  2 ,  Chiara Sabatini  2 ,  Marco Lanza  2 ,  Gianfranco Caselli  2 ,  Francesco Makovec  2 ,  Maria Sbraccia  3 ,  Paola Molinari  3 ,  Tommaso Costa  3 ,  Andrea Cappelli  1
Affiliations
  • 1. Dipartimento di Biotecnologie , Chimica e Farmacia and European Research Centre for Drug Discovery and Development , Università degli Studi di Siena , Via A. Moro 2 , 53100 Siena , Italy . Email: [email protected] ; ; Tel: +39 0577 234320.
  • 2. Rottapharm Biotech S.r.l. , Via Valosa di Sopra 3 , 20900 Monza , Italy.
  • 3. Dipartimento di Farmacologia , Istituto Superiore di Sanità , Viale Regina Elena 299 , 00161 Roma , Italy.
PMID: 30108781 DOI: 10.1039/c6md00458j
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.

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