Review of 5-HT4R Ligands: State of Art and Clinical Applications

Abstract

This article reviews the medicinal implications of 5-HT(4)R in the peripheral and central nervous systems, based on data from two hundred bibliographic references. An exhaustive compilation of molecules reported to be antagonists or agonists for 5-HT(4)R is presented, including chemical structures, binding properties and pharmacological profiles. In the last part of the review, some key concepts concerning structure-activity relationships are highlighted.

Cross-Species Translational Findings in the Discriminative Stimulus Effects of Ethanol

“…However, there are inconsistencies in the generalizability of 5-HT 1B/2C agonists to substitute for ethanol across sex and species, as RU 24969 only partially substituted for ethanol in female rats [36] and mCPP did not generalize from ethanol in mice [64]. Refinement of receptor ligands with increased selectivity for 5-HT 1 and 5-HT 2 receptor isoforms (e.g., [69, 70]) coupled with a rapid expansion of novel ligand development for 5-HT 4 receptors, which also function to regulate neurotransmission in conjunction with 5-HT 1 and 5-HT 2 receptors [71, 72], should prompt a fresh look at the involvement of metabotropic 5-HT receptors in modulating the discriminative stimulus effects of ethanol.…”

A Hybrid Structural Approach to Analyze Ligand Binding by the Serotonin Type 4 Receptor (5-HT4)

“…DISCUSSION 5-HT4R is a serotonin receptor subtype that can be expressed and purified to reasonable purity and homogeneity. In addition, the pharmacokinetics of its ligand interactions have been well studied (37) making it an excellent model system for exploring GPCR structure-function. In this study, we analyzed the ligand binding properties of a physiologically active form of 5-HT4R that was stable under various experimental conditions.…”

Synthesis and Structure–Affinity Relationships of Selective High-Affinity 5-HT4 Receptor Antagonists: Application to the Design of New Potential Single Photon Emission Computed Tomography Tracers

“…Previous results have shown that some 5-HT 4 R ligands bearing bulky aromatic group bonded to the lateral chain can exhibit high affinities. 3 Accordingly, compounds 11C and 11d were synthesized. Despite the introduction of the bulky iodoaryl group, the iodinated 4-fluorobenzonaphthyridine 11d was found to exhibit high affinity for both guinea pig 5-HT 4 R (Ki = 2.5 nM) and human 5-HT 4 R (Ki = 0.23 nM) in the similar order of magnitude as compound 4v .…”

“…3,4 Pharmacological investigations coupled to the discovery of ligands exhibiting high affinity and selectivity for 5-HT 4 Rs have led to know their anatomical distribution and functional roles. 5-HT 4 Rs are found in the peripheral system, where they are implicated in gastrointestinal disorders 5 and heart failures 6 .…”