CSTI-300 (SMP-100); a Novel 5-HT3 Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome

Roberts, Alexander and Grafton, Gillian and Powell, Andrew D. and Brock, Kristian and Chen, Chunlin and Xie, Dejian and Huang, Jinkun and Liu, Shuang and Cooper, Alison J and Brady, Catherine A and Qureshi, Omar and Stamataki, Zania and Manning, David D and Moore, Nicholas A and Sargent, Bruce J and Guzzo, Peter R and Barnes, Nicholas M (2020) CSTI-300 (SMP-100); a Novel 5-HT3 Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome. The Journal of Pharmacology and Experimental Therapeutics, 373 (1). pp. 122-134. ISSN 1521-0103

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Abstract

The 5-hydroxytryptamine (5-HT; serotonin) 5-HT 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-HT 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 and 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-HT receptor (K approximately 2.0 nM) and acted as a partial agonist (approximately 30-50% intrinsic efficacy) In an 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 value for the 5-HT 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 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-HT 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-HT receptor is thought to be implicated in the pathophysiology. As 5-HT receptor blockade with antagonists results in significant side effects, we present evidence that treatment with a suitable 5-HT 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. [Abstract copyright: The American Society for Pharmacology and Experimental Therapeutics.]

Item Type:	Article
Additional Information:	** From PubMed via Jisc Publications Router ** History: received 26-06-2019; revised 23-01-2020; accepted 24-01-2020.
Identification Number:	10.1124/jpet.119.261008
Dates:	Date Event 24 January 2020 Accepted 26 February 2020 Published
Uncontrolled Keywords:	5-HT receptors, bowel disorders, drug discovery, gastrointestinal motility, intestinal motility, ligand gated ion channels
Subjects:	CAH02 - subjects allied to medicine > CAH02-04 - nursing and midwifery > CAH02-04-01 - nursing (non-specific)
Divisions:	Faculty of Health, Education and Life Sciences > College of Health and Care Professions
SWORD Depositor:	JISC PubRouter
Depositing User:	JISC PubRouter
Date Deposited:	15 Jun 2020 11:02
Last Modified:	03 Mar 2022 15:37
URI:	https://www.open-access.bcu.ac.uk/id/eprint/9014

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