Investigating the pharmacology of novel 5-HT3 receptor ligands; with the potential to treat neuropsychiatric and gastrointestinal disorders

[摘要] The 5-hydroxytryptamine (5-HT; serotonin) 5-HT3 receptor is an excitatory ligand-gated ion channel expressed in for example the brain and the gastrointestinal tract.Two major subtypes of the receptor have been studied in the most detail; the homomeric 5-HT3A receptor and the heteromeric 5-HT3AB receptor.5-HT3 receptor antagonists are used clinically to treat chemotherapy induced and post-operative nausea and vomiting, and demonstrate symptomatic relief in diarrhoea-predominant irritable bowel syndrome (IBS-d); but unfortunately, these medications cause adverse effects such as constipation or rarely ischemic colitis in the latter condition.This study has characterised the pharmacology of two structurally distinct 5-HT3 receptor partial agonists (vortioxetine and CSTI-300); and identified the unique binding properties of the cryptic orthosteric modulator 5-chloroindole (Cl-indole) for the human (h) 5-HT3 receptor. Vortioxetine is a multi-modal antidepressant, which displays affinity for the 5-HT transporter as well as a multitude of 5-HT receptors, including the 5-HT3 receptor.The first part of this study has identified vortioxetine as a relatively high affinity, competitive 5-HT3 receptor partial agonist with an intrinsic efficacy of approximately 40-50% that of 5-HT.Given the safety of vortioxetine in patients, it has the potential to be trialled in other conditions for which 5-HT3 receptor antagonists demonstrate efficacy but cause adverse effects, such as IBS-d or even schizophrenia.The second section of this study has identified CSTI-300 as a selective, high affinity 5-HT3 receptor partial agonist (intrinsic activity 30-40% that of 5-HT).Moreover, in a rodent model of IBS-d, CSTI-300 demonstrated comparable efficacy to alosetron, a 5-HT3 receptor antagonist with established efficacy in treating IBS-d. CSTI-300 is predicted to be able to relieve symptoms of IBS-d in patients without eliciting the side effect profile associated with 5-HT3 receptor antagonism.The final part of this study has demonstrated that the binding mechanism of Cl-indole for the 5-HT3A receptor is modulated by 5-HT3 receptor agonists, but not 5-HT3 receptor antagonists.This could have implications in designing 5-HT3 receptor allosteric ligands for potentially treating conditions such as IBS-d.

[发布机构] University:University of Birmingham;Department:Institute of Clinical Sciences

[关键词] Q Science;QP Physiology