Bivalent Ligands for the Serotonin 5-HT3 Receptor

The serotonin 5-HT3 receptor is a ligand-gated ion channel, which by virtue of its pentameric architecture, canbe considered to be an intriguing example of intrinsicallymultivalent biological receptors. This paper describes a generaldesign approach to the study of multivalency in this multimericion channel. Bivalent ligands for 5-HT3 receptor have beendesigned by linking an arylpiperazine moiety to probes showing different functional features. Both homobivalent and hetero- bivalent ligands have shown 5-HT3 receptor affinity in the nanomolar range, providing evidence for the viability of our design approach. Moreover, the high affinity shown by homo- bivalent ligands suggests that bivalency is a promising approachin 5-HT3 receptor modulation and provides the rational basis for applying the concepts of multivalency to the study of 5-HT3 receptor function.