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Journal of Pharmacology and Experimental Therapeutics 2020-Feb

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

يمكن للمستخدمين المسجلين فقط ترجمة المقالات
الدخول التسجيل فى الموقع
يتم حفظ الارتباط في الحافظة
Alexander Roberts
Gillian Grafton
Andrew Powell
Kristian Brock
Chunlin Chen
Dejian Xie
Jinkun Huang
Shuang Liu
Alison Cooper
Catherine Brady

الكلمات الدالة

نبذة مختصرة

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 (Ki 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 Ki 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 t1/2 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.

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