Allosteric modulation of the 5-HT3 receptor

Abstract

5-Hydroxytryptamine type 3 (5-HT 3 ) receptors are ligand-gated ion channels that play important roles in depression, anxiety, substance abuse, emesis, inflammatory pain, spinal nociception, gastrointestinal function, and cardiovascular reflexes. Probably the most studied modulators of 5-HT 3 receptors are the high affinity competitive 'setron' antagonists typified by ondansetron. However, there exists a broad range of compounds that modulate the 5-HT 3 receptor, not through the orthosteric site but by binding to allosteric sites. Most notable are therapeutic compounds ascribed to certain targets but that allosterically modulate 5-HT 3 receptors at clinically relevant concentrations.

Seeking Structural Specificity: Direct Modulation of Pentameric Ligand-Gated Ion Channels by Alcohols and General Anesthetics

“…A variety of pentameric ligand-gated ion channels have been implicated in directly mediating physiologic effects of alcohols and anesthetics (Campagna et al, 2003), consistent with the prominence of these receptors in both inhibitory and excitatory neurotransmission related to processes, such as reward, consciousness, nociception, mobility, and learning and memory Davies, 2011;Miwa et al, 2011;Changeux, 2012;Dutertre et al, 2012). Indeed, the diversity of both enhancing and inhibitory responses to allosteric ABBREVIATIONS: ELIC, Erwinia chrysanthemi ligand-gated ion channel; GLIC, Gloeobacter violaceus ligand-gated ion channel; GluCl, glutamate-gated chloride channel; M1-M4, transmembrane helices 1-4; PDB, Protein Data Bank; 6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylate.…”

“…Serotonin 3 Receptors. Ionotropic serotonin receptors in brain primarily include homomeric 5-HT 3A and heteromeric 5-HT 3A/B ion channels, which mediate excitatory neurotransmission in processes such as nausea, anxiety, and seizure; accordingly, 5-HT 3 receptor antagonists have been shown to combat these and other symptoms related to alcoholism (Davies, 2011). Similar to their effects on nicotinic receptors, long-chain n-alcohols inhibited 5-HT 3 receptors, whereas short-chain alcohols and several volatile anesthetics potentiated channel function (Machu and Harris, 1994;Jenkins et al, 1996).…”

In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)

“…[49,50] These compounds illicit similar effects on the 5-HT3 receptor. [11] Since the structure of one such anesthetic, lidocaine, had a degree of structural similarity to serotonin and the ginger compounds, our study focused on the latter allosteric site. The orientation of the docked ligands within the allosteric binding site is depicted in Figure 10A with contoured surface coloured according to lipophilic character ( Figure 11B).…”

Discovery of a Novel Allosteric Modulator of 5-HT3 Receptors

“…Numerous positive and negative allosteric modulators (PAMs and NAMs, respectively) of Cys-loop receptors have been identified, and new generations of allosteric modulators of GABA A Rs and nAChRs comprise several potent and selective drugs and highly interesting pharmacological tools (5, 6, 16 -18). In contrast, the allosteric modulators of 5-HT 3 Rs reported to date, including n-alcohols, volatile and intravenous anesthetics, and various antidepressants and antipsychotics, are all characterized by promiscuous pharmacological profiles and by displaying low potencies at the 5-HT 3 Rs (19).…”