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Multivalent ligands for the serotonin 5-HT₄ receptor.

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.

SUBMITTER: Castriconi F

PROVIDER: S-EPMC6071950 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Multivalent ligands for the serotonin 5-HT4 receptor.

Castriconi Federica F Paolino Marco M Donati Alessandro A Giuliani Germano G Anzini Maurizio M Mennuni Laura L Sabatini Chiara C Lanza Marco M Caselli Gianfranco G Makovec Francesco F Sbraccia Maria M Molinari Paola P Costa Tommaso T Cappelli Andrea A

MedChemComm 20170209 3

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 i ...[more]

PMID: 30108781

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