CSTI-300; a novel 5-HT3 receptor partial agonist with potential to treat patients with irritable bowel syndrome or carcinoid syndrome.

The 5-hydroxytryptamine (5-HT; serotonin) 5-HT₃ receptor represents a clinical target for antagonists to deliver symptomatic relief to patients with diarrhoea-predominant irritable bowel syndrome (IBS-d) or carcinoid syndrome. Unfortunately, this pharmacological strategy can present side effects (e.g. severe constipation). The present study investigates the potential of a novel 5-HT₃ receptor partial agonist, CSTI-300, to treat patients with IBS-d, and other conditions associated with discomfort from colonic distension, with a predicted reduced side-effect profile. The in vitro and in vivo pre-clinical pharmacology of the drug CSTI-300 was investigated to explore the potential to treat patients with IBS-d. CSTI-300 displayed selective high affinity for the human (h) and rat (r) 5-HT₃ receptor (K_i approximately 2.0 nM) and acted as a partial agonist (approximately 30-50% intrinsic efficacy) in vitro In an in vivo model of IBS-d, the rat colon distension model, CSTI-300 displayed dose-dependent efficacy. In addition, oral administration of CSTI-300 to dogs that achieved plasma levels of the drug exceeding the K_i value for the 5-HT₃ receptor failed to either evoke emesis or alter the state of faeces. Pharmacokinetics for CSTI-300 in rat and dog identified high levels of oral availability with t_1/2 range of 1.6-4.4 hours. The pre-clinical pharmacology of the Lead Candidate drug, CSTI-300, supports the potential of this novel drug to offer symptomatic relief to patients with IBS and carcinoid syndrome with a rationale for a reduced 'on-target' side-effect profile relative to 5-HT₃ receptor antagonists such as alosetron. SIGNIFICANCE STATEMENT: There is a lack of effective current treatment for IBS-d and carcinoid syndrome, and in both conditions, over-activity of the 5-HT₃ receptor is thought to be implicated in the pathophysiology. As 5-HT₃ receptor blockade with antagonists results in significant side effects, we present evidence that treatment with a suitable 5-HT₃ receptor partial agonist will alleviate some symptoms associated with these conditions yet without fully inhibiting the receptor predict a less pronounced side effect profile associated with this therapeutic strategy.