Bivalent Ligands for the Serotonin 5-HT₃ Receptor

Abstract

The serotonin 5-HT3 receptor is a ligand-gated ion channel, which by virtue of its pentameric architecture, can be considered to be an intriguing example of intrinsically multivalent biological receptors. This paper describes a general design approach to the study of multivalency in this multimeric ion channel. Bivalent ligands for 5-HT3 receptor have been designed by linking an arylpiperazine moiety to probes showing different functional features. Both homobivalent and heterobivalent 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 homobivalent ligands suggests that bivalency is a promising approach in 5-HT3 receptor modulation and provides the rational basis for applying the concepts of multivalency to the study of 5-HT3 receptor function.

Multivalent ligands for the serotonin 5-HT4 receptor

“…Consistent with our research on development of 5-HT receptor ligands, [11][12][13][14][15][16][17] we evaluated a series of new multivalent 5-HT 4 R ligands. Following the guidance of Berque-Bestel et al, 8,9 we used the same protomeric unit (i.e., 2, tethered at the 4-position of the piperidine moiety) as an active entity, because a partial agonist would facilitate detection of a potential increase of efficacy.…”

Two for the Price of One: Heterobivalent Ligand Design Targeting Two Binding Sites on Voltage-Gated Sodium Channels Slows Ligand Dissociation and Enhances Potency

“… 51 , 52 For example, an engineered homobivalent protein kinase inhibitor had 100-fold higher potency for a particular subgroup of kinases, 53 and a homobivalent agonist targeting oxytocin receptor homodimers displayed potency that was ∼1000-fold greater than that of its monovalent counterpart. 54 Heterobivalent and multivalent ligands with improved potency have also been developed against the 5-HT 3 receptor 55 and the nicotinic acetylcholine receptor, 56 respectively.…”

Discriminating between 5‐HT3A and 5‐HT3AB receptors

“…To this end, Cappelli and co‐workers have modified the physicochemical properties of 5‐HT 3 R ligands to prevent them from crossing the blood brain barrier (Butini et al ., ; Morelli et al ., ; Cappelli et al ., ; Modica et al ., ). Ligands with activities at more than one receptor have also been described by the same group, and have the potential for treating disorders with complex aetiologies (Morelli et al ., ; Cappelli et al ., ). New ligands are still being discovered, and fragment library screens have recently been used to successfully identify novel allosteric modulators and competitive antagonists, with at least one showing 5‐HT 3 R subtype selectivity.…”